U.S. patent number 10,034,886 [Application Number 15/711,858] was granted by the patent office on 2018-07-31 for glp-1 receptor modulators.
This patent grant is currently assigned to Celgene International II S RL. The grantee listed for this patent is Celgene International II S RL. Invention is credited to Marcus F. Boehm, Enugurthi Brahmachary, Thomas Fowler, Daniel Glynn, Liming Huang, Michael Knaggs, Esther Martinborough, Premji Meghani, Mark Mills, Manisha Moorjani, Andrew Novak, Junko Tamiya, Adam R. Yeager.
United States Patent |
10,034,886 |
Boehm , et al. |
July 31, 2018 |
GLP-1 receptor modulators
Abstract
Compounds are provided that modulate the glucagon-like peptide 1
(GLP-1) receptor, as well as methods of their synthesis, and
methods of their therapeutic and/or prophylactic use. Such
compounds can act as modulators or potentiators of GLP-1 receptor
on their own, or with incretin peptides such as GLP-1(7-36) and
GLP-1(9-36), or with peptide-based therapies, such as exenatide and
liraglutide, and have the following general structure (where ""
represents either or both the R and S form of the compound):
##STR00001## where A, B, C, Y.sub.1, Y.sub.2, Z, R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, W.sub.1, n, p and q are as defined
herein.
Inventors: |
Boehm; Marcus F. (San Diego,
CA), Martinborough; Esther (San Diego, CA), Moorjani;
Manisha (San Diego, CA), Tamiya; Junko (Carlsbad,
CA), Huang; Liming (San Diego, CA), Yeager; Adam R.
(La Mesa, CA), Brahmachary; Enugurthi (San Diego, CA),
Fowler; Thomas (Melton Mowbray, GB), Novak;
Andrew (Long Eaton, GB), Meghani; Premji
(Loughborough, GB), Knaggs; Michael (Burton-on-Trent,
GB), Glynn; Daniel (Sneinton, GB), Mills;
Mark (Carlton, GB) |
Applicant: |
Name |
City |
State |
Country |
Type |
Celgene International II S RL |
Couvet |
N/A |
CH |
|
|
Assignee: |
Celgene International II S RL
(Couvet, CH)
|
Family
ID: |
55069126 |
Appl.
No.: |
15/711,858 |
Filed: |
September 21, 2017 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20180021346 A1 |
Jan 25, 2018 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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14965777 |
Dec 10, 2015 |
9795613 |
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62090268 |
Dec 10, 2014 |
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62161658 |
May 14, 2015 |
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62164113 |
May 20, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D
231/12 (20130101); A61P 1/16 (20180101); C07D
211/22 (20130101); C07D 295/084 (20130101); C07D
403/12 (20130101); C07D 285/12 (20130101); A61P
3/04 (20180101); C07D 413/12 (20130101); C07D
213/55 (20130101); A61K 31/44 (20130101); A61K
31/4245 (20130101); A61K 31/506 (20130101); C07D
417/12 (20130101); C07D 211/98 (20130101); C07D
405/12 (20130101); C07D 471/04 (20130101); C07D
241/12 (20130101); A61K 31/4439 (20130101); A61K
31/551 (20130101); C07D 413/04 (20130101); A61K
31/402 (20130101); A61K 31/445 (20130101); C07D
285/08 (20130101); C07D 403/04 (20130101); A61K
31/4468 (20130101); C07D 239/34 (20130101); A61K
31/426 (20130101); A61K 31/4178 (20130101); C07D
253/065 (20130101); C07D 407/12 (20130101); A61K
31/4725 (20130101); A61K 31/4965 (20130101); C07D
237/08 (20130101); C07D 271/06 (20130101); C07D
409/14 (20130101); A61P 3/00 (20180101); C07D
239/26 (20130101); C07D 295/135 (20130101); C07D
401/12 (20130101); C07D 403/10 (20130101); A61K
31/433 (20130101); A61K 38/26 (20130101); C07D
277/30 (20130101); A61K 31/501 (20130101); C07D
495/04 (20130101); A61K 31/4545 (20130101); C07D
401/06 (20130101); A61K 31/454 (20130101); C07D
241/08 (20130101); C07D 243/08 (20130101); A61K
31/4709 (20130101); A61K 31/495 (20130101); A61P
43/00 (20180101); A61K 31/53 (20130101); C07D
207/08 (20130101); A61K 31/421 (20130101); A61P
25/00 (20180101); C07D 263/32 (20130101); A61K
31/505 (20130101); C07D 253/06 (20130101); C07D
271/107 (20130101); C07D 215/14 (20130101); C07D
409/12 (20130101); A61P 3/10 (20180101); C07D
401/04 (20130101); C07D 239/74 (20130101); A61K
31/50 (20130101); A61K 31/497 (20130101) |
Current International
Class: |
A61K
31/506 (20060101); C07D 285/08 (20060101); C07D
277/30 (20060101); C07D 271/107 (20060101); C07D
239/74 (20060101); C07D 239/34 (20060101); C07D
239/26 (20060101); C07D 237/08 (20060101); C07D
231/12 (20060101); C07D 215/14 (20060101); C07D
213/55 (20060101); C07D 211/98 (20060101); C07D
211/22 (20060101); C07D 207/08 (20060101); A61K
38/26 (20060101); A61K 31/53 (20060101); A61K
31/505 (20060101); A61K 31/501 (20060101); A61K
31/50 (20060101); A61K 31/4965 (20060101); A61K
31/497 (20060101); A61K 31/4709 (20060101); C07D
271/06 (20060101); C07D 263/32 (20060101); C07D
253/065 (20060101); C07D 253/06 (20060101); C07D
243/08 (20060101); C07D 241/12 (20060101); C07D
241/08 (20060101); C07D 403/10 (20060101); A61K
31/551 (20060101); A61K 31/4725 (20060101); A61K
31/495 (20060101); A61K 31/4545 (20060101); A61K
31/454 (20060101); A61K 31/4468 (20060101); A61K
31/4439 (20060101); A61K 31/445 (20060101); A61K
31/44 (20060101); A61K 31/433 (20060101); A61K
31/4245 (20060101); A61K 31/426 (20060101); A61K
31/421 (20060101); A61K 31/4178 (20060101); C07D
495/04 (20060101); C07D 471/04 (20060101); A61K
31/402 (20060101); C07D 417/12 (20060101); C07D
413/12 (20060101); C07D 413/04 (20060101); C07D
409/14 (20060101); C07D 409/12 (20060101); C07D
407/12 (20060101); C07D 405/12 (20060101); C07D
403/12 (20060101); C07D 403/04 (20060101); C07D
401/12 (20060101); C07D 401/06 (20060101); C07D
401/04 (20060101); C07D 295/135 (20060101); C07D
295/084 (20060101); C07D 285/12 (20060101) |
Field of
Search: |
;544/333,335
;514/256 |
References Cited
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WO |
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WO |
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WO |
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WO |
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WO |
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|
Primary Examiner: Rao; Deepak R
Attorney, Agent or Firm: Seed IP Law Group LLP
Claims
We claim:
1. A method of treating type II diabetes, non-alcoholic fatty liver
disease or non-alcoholic steatohepatitis in a patient, comprising
administering to the patient an effective amount of a compound
having one of the following structures: ##STR01973## or a
pharmaceutically acceptable diastereomer, enantiomer, racemate,
salt, hydrate or solvate thereof, wherein R.sub.2 is
--NR.sub.41R.sub.42; R.sub.3 is alkyl, alkyl substituted with
cyano, or --S(O.sub.2)(alkyl); R.sub.41 and R.sub.42 taken together
with the N atom to which they are attached form a 4-membered
heterocyclyl substituted with --COOH; and R.sub.5 is cycloalkyl
optionally substituted singly or multiply with halo, alkyl or
haloalkyl.
2. The method of claim 1 wherein the malcondition is type II
diabetes.
3. The method of claim 1 wherein the malcondition is non-alcoholic
fatty liver disease.
4. The method of claim 1 wherein the malcondition is non-alcoholic
steatohepatitis.
5. The method of claim 1, wherein R.sub.41 and R.sub.42 taken
together with the N atom to which they are attached form a
4-membered heterocyclyl having the following structure:
##STR01974##
6. The method of claim 1, wherein 4-membered heterocyclyl is
substituted with --COOH to provide the following structure:
##STR01975##
7. The method of claim 1, wherein R.sub.3 is ethyl, iso-propyl,
cyclopropyl, iso-butyl or tert-butyl.
8. The method of claim 1, wherein R.sub.3 is ethyl, iso-propyl,
cyclopropyl, iso-butyl or tert-butyl, each of which is substituted
with cyano.
9. The method of claim 1, wherein R.sub.3 is
--SO.sub.2CH.sub.3.
10. The method of claim 1, wherein R.sub.5 is cyclohexyl singly or
multiply substituted with halo, alkyl or haloalkyl.
11. The method of claim 1, wherein R.sub.5 is cyclohexyl singly
substituted with alkyl.
12. The method of claim 1, wherein R.sub.5 is cyclohexyl singly
substituted with methyl, ethyl, n-propyl, iso-propyl or
tert-butyl.
13. The method of claim 1, wherein R.sub.5 is cyclohexyl singly or
multiply substituted with halo or haloalkyl.
14. The method of claim 1, wherein the compound has the structure
of any one of the following compounds, or a pharmaceutically
acceptable diastereomer, enantiomer, racemate, salt, hydrate or
solvate thereof ##STR01976## ##STR01977## ##STR01978## ##STR01979##
##STR01980## ##STR01981## ##STR01982## ##STR01983## ##STR01984##
Description
STATEMENT REGARDING SEQUENCE LISTING
The Sequence Listing associated with this application is provided
in text format in lieu of a paper copy, and is hereby incorporated
by reference into the specification. The name of the text file
containing the Sequence Listing is
800059_412D1_SEQUENCE_LISTING.txt. The text file is 1.72 KB, was
created on Sep. 21, 2017, and is being submitted electronically via
EFS-Web.
FIELD OF THE INVENTION
The invention relates to compounds that bind the glucagon-like
peptide 1 (GLP-1) receptor, methods of their synthesis, and methods
of their therapeutic and/or prophylactic use. The present invention
is directed to compounds adapted to act as modulators of the GLP-1
receptor, and potentiators of incretin peptides, such as
GLP-1(7-36) and GLP-1(9-36), and oxyntomodulin, as well as
peptide-based therapies such as exenatide and liraglutide.
BACKGROUND
Glucagon-like peptide 1 receptor (GLP-1R) belongs to Family B1 of
the seven-transmembrane G protein-coupled receptors, and its
natural agonist ligand is the peptide hormone glucagon-like
peptide-1 (GLP-1). GLP-1 is a peptide hormone arising by its
alternative enzymatic cleavage from proglucagon, the prohormone
precursor for GLP-1, which is highly expressed in enteroendocrine
cells of the intestine, the alpha cells of the endocrine pancreas
(islets of Langerhans), and the brain (Kieffer T. J. and Habener,
J. F. Endocrin. Rev. 20:876-913 (1999); Drucker, D. J.,
Endocrinology 142:521-7 (2001); Holst, J. J., Diabetes Metab. Res.
Rev. 18:430-41 (2002)). The initial actions of GLP-1 observed were
on the insulin-producing cells of the islets, where it stimulates
glucose-dependent insulin secretion. Subsequently, multiple
additional antidiabetogenic actions of GLP-1 were discovered
including the stimulation of the growth and inhibition of the
apoptosis of pancreatic beta cells (Drucker, D. J., Endocrinology
144:5145-8 (2003); Holz, G. G. and Chepurny O. G., Curr. Med. Chem.
10:2471-83 (2003); List, J. F. and Habener, J. F., Am. J. Physiol.
Endocrinol. Metab. 286:E875-81 (2004)).
Like GLP-1, Oxyntomodulin is also generated from L-cell derived
proglucagon by alternative proteolysis. Oxyntomodulin is identical
to glucagon plus an additional 8 amino acid carboxyterminal
extension (Bataille D., et al, Peptides 2 Suppl s:41-4 (1981)).
Oxyntomodulin is a dual agonist of both GLP-1 receptor and glucagon
receptor. Oxyntomodulin induces glucose dependent insulin secretion
from pancreatic .beta. cells (Maida, A., et al, Endocrinology
149:5670-8 (2008), and in vivo, oxyntomodulin modulates food intake
(Dakin, C. L. et al, Endocrinology 142:4244-50 (2001)) and is
significantly anorectic (Baggio, L. L. et al, Gastroenterology
127:46-58 (2004)).
On activation, GLP-1 receptors couple to the .alpha.-subunit of G
protein, with subsequent activation of adenylate cyclase and
increase of cAMP levels, thereby potentiating glucose-stimulated
insulin secretion. Therefore, GLP-1 is an attractive therapeutic
target to lower blood glucose and preserve the .beta.-cells of the
pancreas of diabetic patients. Glucagon has been used for decades
in medical practice within diabetes and several glucagon-like
peptides are being developed for various therapeutic indications.
GLP-1 analogs and derivatives are being developed for the treatment
for patients suffering from diabetes.
SUMMARY OF THE INVENTION
The present invention is directed to compounds adapted to act as
potentiators or modulators of GLP-1 receptor; methods of their
preparation and methods of their use, such as in treatment of a
malcondition mediated by GLP-1 receptor activation, or when
modulation or potentiation of GLP-1 receptor is medically
indicated.
Certain embodiments of the present invention comprise a compound
having the structure of Formula I-R or I-S or a pharmaceutically
acceptable isomer, enantiomer, racemate, salt, isotope, prodrug,
hydrate or solvate thereof:
##STR00002## wherein A is a 5-, 6- or 7-membered heterocyclyl
having one, two or three heteroatoms where each such heteroatom is
independently selected from O, N, and S, and where any ring atom of
such heterocyclyl may be optionally substituted with one or more of
R.sub.4; B is aryl, aralkyl, heterocyclyl, or heterocyclylalkyl; C
is aryl, aralkyl, heterocyclyl or heterocyclylalkyl, and when C is
aryl A and C may be taken together to form a fused bicyclic ring
system between the 5-, 6- or 7-membered heterocyclyl of A and the
aryl of C; Y.sub.1 and Y.sub.2 are both null, or one of Y.sub.1 or
Y.sub.2 is --NH-- or --O-- and the other Y.sub.1 or Y.sub.2 is
null; Z is --C(O)-- or --S(O).sub.2--; each R.sub.1 is
independently H or C.sub.1-4 alkyl; R.sub.2 is --OH, --O--R.sub.8,
--N(R.sub.1)--SO.sub.2--R.sub.7, --NR.sub.41R.sub.42,
--N(R.sub.1)--(CR.sub.aR.sub.b).sub.m--COOR.sub.8,
--N(R.sub.1)--(CR.sub.aR.sub.b).sub.m--CO--N(R.sub.1)(R.sub.40),
--N(R.sub.1)--(CR.sub.aR.sub.b).sub.m--N(R.sub.1)C(O)O(R.sub.8),
--N(R.sub.1)--(CR.sub.aR.sub.b).sub.m--N(R.sub.1)(R.sub.40),
--N(R.sub.1)--(CR.sub.aR.sub.b).sub.m--CO--N(R.sub.1)-heterocyclyl,
or --N(R.sub.1)--(CR.sub.aR.sub.b).sub.m-heterocyclyl, which
heterocyclyl may be optionally (singly or multiply) substituted
with R.sub.7; each R.sub.3 and R.sub.4 is independently H, halo,
alkyl, alkyl substituted (singly or multiply) with R.sub.31,
alkoxy, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, aryl,
heterocyclyl, --OH, --OR.sub.7, --CN, --NO.sub.2,
--NR.sub.1R.sub.7, --C(O)R.sub.7, --C(O)NR.sub.1R.sub.7,
--NR.sub.1C(O)R.sub.7, --SR.sub.7, --S(O)R.sub.7,
--S(O).sub.2R.sub.7, --OS(O).sub.2R.sub.7,
--S(O).sub.2NR.sub.1R.sub.7, --NR.sub.1S(O).sub.2R.sub.7,
--(CR.sub.aR.sub.b).sub.mNR.sub.1R.sub.7,
--(CR.sub.aR.sub.b).sub.mO(CR.sub.aR.sub.b).sub.mR.sub.7,
--(CR.sub.aR.sub.b).sub.mNR.sub.1(CR.sub.aR.sub.b).sub.mR.sub.7 or
--(CR.sub.aR.sub.b).sub.mNR.sub.1(CR.sub.aR.sub.b).sub.mCOOR.sub.8;
or any two R.sub.3 or R.sub.4 groups on the same carbon atom taken
together form oxo; each R.sub.31 is independently H, halo,
hydroxyl, --NR.sub.41R.sub.42, or alkoxy; each R.sub.40 is
independently H, R.sub.7, alkyl which may be optionally (singly or
multiply) substituted with R.sub.7, or R.sub.40 and R.sub.1 taken
together with the N atom to which they are attached form a 3- to
7-membered heterocyclyl which may be optionally (singly or
multiply) substituted with R.sub.7; each R.sub.41 and R.sub.42 is
independently R.sub.40, --(CHR.sub.40).sub.n--C(O)O--R.sub.40,
--(CHR.sub.40).sub.n--C(O)--R.sub.40,
--(CH.sub.2).sub.n--N(R.sub.1)(R.sub.7), aryl or heteroaryl any of
which aryl or heteroaryl may be optionally (singly or multiply)
substituted with R.sub.7; or any two R.sub.41 and R.sub.42 taken
together with the N atom to which they are attached form a 3- to
7-membered heterocyclyl which may be optionally (singly or
multiply) substituted with R.sub.7; W.sub.1 is null or
-L.sub.1-(CR.sub.aR.sub.b).sub.m-L.sub.1-R.sub.6; each L.sub.1 is
independently, from the proximal to distal end of the structure of
Formula I-R or I-S, null, --C(O)O--, --S(O.sub.2)--, --S(O)--,
--S--, --N(R.sub.1)--C(O)--N(R.sub.1)--, --N(R.sub.1)--C(O)--O--,
--C(O)-- or --S(O.sub.2)--NR.sub.1--; each R.sub.a and R.sub.b is
independently H, halo, alkyl, alkoxy, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl (any of which alkyl, alkoxy, aryl, aralkyl,
heterocyclyl or heterocyclylalkyl may be optionally (singly or
multiply) substituted with R.sub.7,
--(CHR.sub.40).sub.mC(O)OR.sub.40, --(CHR.sub.40).sub.mOR.sub.40,
--(CHR.sub.40).sub.mSR.sub.40,
--(CHR.sub.40).sub.mNR.sub.41R.sub.42,
--(CHR.sub.40).sub.mC(O)NR.sub.41R.sub.42,
--(CHR.sub.40).sub.mC(O)N(R.sub.1)(CHR.sub.40).sub.mNR.sub.41R.sub.42,
--(CHR.sub.40).sub.mC(O)N(R.sub.1)(CHR.sub.40).sub.mC(O)NR.sub.41R.sub.42-
,
--(CHR.sub.40).sub.mC(O)N(R.sub.1)--(CHR.sub.40).sub.mC(O)OR.sub.40,
or --(CHR.sub.40).sub.m--S--S--R.sub.40; or any two R.sub.a and
R.sub.b taken together with the carbon atom(s) to which they are
attached form a cycloalkyl or heterocyclyl optionally substituted
(singly or multiply) with R.sub.7; or R.sub.1 and any one of
R.sub.a or R.sub.b taken together with the atoms to which they are
attached form heterocyclyl optionally substituted (singly or
multiply) with R.sub.7; R.sub.5 is R.sub.7,
--(CR.sub.aR.sub.b).sub.m--(CR.sub.aR.sub.b).sub.m--R.sub.7, or
-(-L.sub.3-(CR.sub.aR.sub.b).sub.r-L.sub.3-R.sub.7, wherein the
carbon atoms of any two adjacent --(CR.sub.aR.sub.b).sub.m or
(CR.sub.aR.sub.b).sub.r groups may be taken together to form a
double bond (--(C(R.sub.a).dbd.(C(R.sub.a)--) or triple bond
(--C.ident.C--); R.sub.6 is H, alkyl, aryl, heteroaryl,
heterocyclyl, heterocycloalkyl, any of which may be optionally
substituted (singly or multiply) with R.sub.7 or
--(CR.sub.aR.sub.b).sub.m-L.sub.2-(CR.sub.aR.sub.b).sub.m--R.sub.7;
each R.sub.7 is independently R.sub.10; a ring moiety selected from
cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl, where
such ring moiety is optionally (singly or multiply) substituted
with R.sub.10; or when a carbon atom bears two R.sub.7 groups such
two R.sub.7 groups are taken together to form oxo or thioxo, or are
taken together to form a ring moiety selected from cycloalkyl,
aryl, heterocyclyl or heterocyclyl, wherein such ring moiety is
optionally singly or multiply substituted with R.sub.10; each
R.sub.10 is independently H, halo, alkyl, haloalkyl, haloalkoxy,
perhaloalkyl, perhaloalkoxy, --(CR.sub.aR.sub.b).sub.mOH,
--(CR.sub.aR.sub.b).sub.mOR.sub.8, --(CR.sub.aR.sub.b).sub.mCN,
--(CR.sub.aR.sub.b).sub.mNH(C.dbd.NH)NH.sub.2,
--(CR.sub.aR.sub.b).sub.mNR.sub.1R.sub.8,
--(CR.sub.aR.sub.b).sub.mO(CR.sub.aR.sub.b).sub.mR.sub.8,
--(CR.sub.aR.sub.b).sub.mNR.sub.1(CR.sub.aR.sub.b).sub.mR.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)R.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)OR.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)NR.sub.1R.sub.8,
--(CR.sub.aR.sub.b).sub.mNR.sub.1(CR.sub.aR.sub.b).sub.mC(O)OR.sub.8,
--(CR.sub.aR.sub.b).sub.mNR.sub.1C(O)R.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)NR.sub.1S(O).sub.2R.sub.8,
--(CR.sub.aR.sub.b).sub.mSR.sub.8,
--(CR.sub.aR.sub.b).sub.mS(O)R.sub.8,
--(CR.sub.aR.sub.b).sub.mS(O).sub.2R.sub.8,
--(CR.sub.aR.sub.b).sub.mS(O).sub.2NR.sub.1R.sub.8 or
--(CR.sub.aR.sub.b).sub.mNR.sub.1S(O).sub.2R.sub.8; each R.sub.8 is
independently H, alkyl, haloalkyl, aryl,
--(CR.sub.aR.sub.b).sub.m-L.sub.2-(CR.sub.aR.sub.b).sub.m--R.sub.1
or -(-L.sub.3-(CR.sub.aR.sub.b).sub.r).sub.s-L.sub.3-R.sub.1;
L.sub.2 is independently, from the proximal to distal end of the
structure of Formula I-R or I-S, null, --O--, --OC(O)--,
--NR.sub.1--, --C(O)NR.sub.1--, --N(R.sub.1)--C(O)--,
--S(O.sub.2)--, --S(O)--, --S--, --C(O)-- or
--S(O.sub.2)--N(R.sub.1)--; each L.sub.3 is independently null,
--O--, or --N(R.sub.1)-- each m is independently 0, 1, 2, 3, 4, 5
or 6; each n is independently 0 or 1 or 2; p is 0, 1, 2 or 3; q is
0, 1, 2 or 3; each r is independently 2, 3, or 4; and each s is
independently 1, 2, 3, or 4.
In certain embodiments, a pharmaceutical composition comprising a
compound of the invention together with at least one
pharmaceutically acceptable carrier, diluent or excipient is
provided.
In certain embodiments, a method of use of a compound of the
invention comprising preparation of a medicament is provided.
In certain embodiments, the invention provides a pharmaceutical
combination comprising a compound of the invention and a second
medicament. In various such embodiments, the second medicament is
an agonist, antagonist, or modulator for glucagon receptor, GIP
receptor, GLP-2 receptor, or PTH receptor, or glucagon-like peptide
1 (GLP-1) receptor. In various such embodiments, the second
medicament is exenatide, liraglutide, taspoglutide, albiglutide, or
lixisenatide or other insulin regulating peptide. In various
embodiments, the second medicament is medically indicated for the
treatment of type II diabetes. In various embodiments, the second
medicament is a biguanide, a sulfonylurea, a meglitinide, a
thiazolidinedione, an .alpha.-glucosidase inhibitor, a bile acid
sequestrant, an SGLT1/2 inhibitor, and/or a dopamine-2 agonist, and
in more specific embodiments is metformin (a biguanide) or
sitagliptin (a DPPIV inhibitor).
In certain embodiments, a method of activation, potentiation or
agonism of a GLP-1 receptor is provided comprising contacting the
receptor with a compound, pharmaceutical composition or
pharmaceutical combination of the invention.
In certain embodiments, a method of potentiating a GLP-1 receptor
is provided comprising contacting the receptor with a compound in
the presense of GLP-1(7-36), GLP-1(9-36) and/or oxyntomodulin.
In certain embodiments, a method is provided for treatment of a
malcondition in a subject for which activation, potentiation or
agonism of a GLP-1 receptor is medically indicated where such
method comprises administering to such subject a compound,
pharmaceutical composition or pharmaceutical combination of the
invention. In various such embodiments, selective activation,
potentiation or agonism of a GLP-1 receptor, is medically
indicated. In various such embodiments, the malcondition comprises
type I diabetes, type II diabetes, gestational diabetes, obesity,
excessive appetite, insufficient satiety, metabolic disorder,
non-alcoholic fatty liver disease and/or non-alcoholic
steatohepatitis.
In certain embodiments, the invention provides methods for
synthesis of certain compounds including compounds of the
invention. In certain other embodiments, the invention provides
certain intermediate compounds associated with such methods of
synthesis.
DETAILED DESCRIPTION OF THE INVENTION
Certain embodiments comprise a compound having the chiral structure
of Formula I-R or I-S (with the chirality as indicated) or a
pharmaceutically acceptable isomer, enantiomer, racemate, salt,
isotope, prodrug, hydrate or solvate thereof:
Certain embodiments of the present invention comprise a compound
having the structure of Formula I-R or I-S or a pharmaceutically
acceptable isomer, enantiomer, racemate, salt, isotope, prodrug,
hydrate or solvate thereof:
##STR00003## where A, B, C, Y.sub.1, Y.sub.2, Z, R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, W.sub.1, n, p and q are as defined
above.
In certain embodiments, the compounds have the structure of Formula
I-R or a pharmaceutically acceptable isomer, enantiomer, salt,
isotope, prodrug, hydrate or solvate thereof. In other embodiments,
the compounds have the structure of Formula I-S or a
pharmaceutically acceptable isomer, enantiomer, salt, isotope,
prodrug, hydrate or solvate thereof.
In certain embodiments, the compounds can be substantially
enantiomerically pure.
In certain embodiments, the invention provides a compound of
Formula I-R and/or Formula I-S where Y.sub.1 and Y.sub.2 are null,
Z is --C(O)-- and A is a 5- or 6-membered heteroaryl group.
Representative compounds of this embodiment include compounds of
the following structures (wherein "" represents either or both the
R and S form of the compound):
##STR00004## ##STR00005## ##STR00006## ##STR00007##
##STR00008##
In certain embodiments, the invention provides a compound where
Y.sub.1 and Y.sub.2 are null, Z is --C(O)-- and A is a 5-, 6- or
7-membered non-aromatic heterocyclyl group. Representative
compounds of this embodiment include compounds of the following
structures (wherein "" represents either or both the R and S form
of the compound):
##STR00009## ##STR00010##
In certain embodiments, the invention provides compounds of each of
structures I-R/S (1)-(29) where R.sub.4 of the phenyl group is
H.
In certain embodiments, the inventions provides compounds of each
of structures I-R/S (1)-(29) where the A group (i.e., the 5-, 6- or
7-membered heterocyclyl) is not substituted by R.sub.4, or
substituted by R.sub.4 where R.sub.4 is alkyl, haloalkyl, alkoxy,
--NR.sub.1R.sub.7 where R.sub.1 and R.sub.7 are independently
hydrogen or alkyl, or substituted by two R.sub.4 groups which taken
together form oxo.
In certain embodiments, the invention provides a compound of
Formula I-R and/or Formula I-S where Y.sub.1 and Y.sub.2 are null,
Z is --C(O)-- and C is aryl. Representative compounds of this
embodiment include compounds of the following structures (wherein
"" represents either or both the R and S form of the compound):
##STR00011##
In certain embodiments, the invention provides compounds of each of
structures I-R/S (30)-(32) where q is zero.
In certain embodiments, the invention provides compounds of each of
structures I-R/S (30)-(32) where q is one, two or three.
In certain embodiments, the invention provides compounds of
structure I-R/S(30) where q is one and R.sub.5 is
--(CR.sub.aR.sub.b).sub.m-L.sub.2-(CR.sub.aR.sub.b).sub.m--R.sub.7
or -(-L.sub.3-(CR.sub.aR.sub.b).sub.r-).sub.s-L.sub.3-R.sub.7.
Representative compounds of this embodiment include compounds of
the following structure (wherein "" represents either or both the R
and S form of the compound):
##STR00012##
In certain embodiments, the invention provides compounds of
structure I-R/S(33) where R.sub.7 is H or alkyl and L.sub.2 is O.
Representative compounds of this embodiment include compounds of
the following structure (wherein "" represents either or both the R
and S form of the compound):
##STR00013##
In certain embodiments, the invention provides compounds of
structure I-R/S(30) where R.sub.5 is R.sub.7. Representative
compounds of this embodiment include compounds of the following
structure (wherein "" represents either or both the R and S form of
the compound):
##STR00014##
In certain embodiments, the invention provides compounds of
structure I-R/S(35) where R.sub.7 is halo, alkyl, haloalkyl,
perhaloalkyl, alkoxy, --(CR.sub.aR.sub.b).sub.mOH,
--(CR.sub.aR.sub.b).sub.mOR.sub.8, --(CR.sub.aR.sub.b).sub.mCN,
--(CR.sub.aR.sub.b).sub.mNH(C.dbd.NH)NH.sub.2,
--(CR.sub.aR.sub.b).sub.mNR.sub.1R.sub.8,
--(CR.sub.aR.sub.b).sub.mO(CR.sub.aR.sub.b).sub.mR.sub.8,
--(CR.sub.aR.sub.b).sub.mNR.sub.1(CR.sub.aR.sub.b).sub.mR.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)R.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)OR.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)NR.sub.1R.sub.8,
--(CR.sub.aR.sub.b).sub.mNR.sub.1(CR.sub.aR.sub.b).sub.mC(O)OR.sub.8,
--(CR.sub.aR.sub.b).sub.mNR.sub.1C(O)R.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)NR.sub.1R.sub.8,
--(CR.sub.aR.sub.b).sub.mSR.sub.8,
--(CR.sub.aR.sub.b).sub.mS(O)R.sub.8, --(CR.sub.aR.sub.b).sub.m
S(O).sub.2R.sub.8,
--(CR.sub.aR.sub.b).sub.mS(O).sub.2NR.sub.1R.sub.8,
--(CR.sub.aR.sub.b).sub.mNR.sub.1S(O).sub.2R.sub.8.
In certain embodiments, the invention provides compounds of
structure I-R/S(35) where R.sub.7 is a ring moiety selected from
cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl, where
such ring moiety is optionally (singly or multiply) substituted
with halo, --OH, --CN, alkyl, alkoxy, haloalkyl or
perhaloalkyl.
In certain embodiments, the invention provides a compound of
Formula I-R and/or Formula I-S where Y.sub.1 and Y.sub.2 are null,
Z is --C(O)-- and C is heterocyclyl. Representative compounds of
this embodiment include compounds of the following structures
(wherein "" represents either or both the R and S form of the
compound):
##STR00015## ##STR00016## ##STR00017##
In certain embodiments, the invention provides compounds of each of
structures I-R/S(36)-(48) where R.sub.7 is halo, alkyl, haloalkyl,
perhaloalkyl, alkoxy, --(CR.sub.aR.sub.b).sub.mOH,
--(CR.sub.aR.sub.b).sub.mOR.sub.8, --(CR.sub.aR.sub.b).sub.mCN,
--(CR.sub.aR.sub.b).sub.mNH(C.dbd.NH)NH.sub.2,
--(CR.sub.aR.sub.b).sub.m NR.sub.1R.sub.8,
--(CR.sub.aR.sub.b).sub.mO(CR.sub.aR.sub.b).sub.mR.sub.8,
--(CR.sub.aR.sub.b).sub.mNR.sub.1(CR.sub.aR.sub.b).sub.mR.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)R.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)OR.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)NR.sub.1R.sub.8,
--(CR.sub.aR.sub.b).sub.mNR.sub.1(CR.sub.aR.sub.b).sub.mC(O)OR.sub.8,
--(CR.sub.aR.sub.b).sub.mNR.sub.1C(O)R.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)NR.sub.1R.sub.8,
--(CR.sub.aR.sub.b).sub.mSR.sub.8,
--(CR.sub.aR.sub.b).sub.mS(O)R.sub.8,
--(CR.sub.aR.sub.b).sub.mS(O).sub.2R.sub.8,
--(CR.sub.aR.sub.b).sub.mS(O).sub.2NR.sub.1R.sub.8,
--(CR.sub.aR.sub.b).sub.mNR.sub.1S(O).sub.2R.sub.8.
In certain embodiments, the invention provides compounds of each of
structures I-R/S(36)-(48) where R.sub.7 is a ring moiety selected
from cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl,
where such ring moiety is optionally (singly or multiply)
substituted with halo, --OH, --CN, alkyl, alkoxy, haloalkyl or
perhaloalkyl.
In certain embodiments, the invention provides a compound of
Formula I-R and/or Formula I-S where Y.sub.1 and Y.sub.2 are null,
Z is --C(O)-- and B is aryl or aralkyl. Representative compounds of
this embodiment include compounds of the following structures
(wherein "" represents either or both the R and S form of the
compound):
##STR00018##
In certain embodiments, the invention provides compounds of each of
structures I-R/S (49)-(52) where W.sub.1 is null.
Representative compounds of this embodiment include compounds of
the following structure (wherein "" represents either or both the R
and S form of the compound):
##STR00019##
In certain embodiments, the invention provides compounds of
structure I-R/S(53) where R.sub.3 is halo, alkyl, alkyl substituted
with R.sub.31, alkoxy, haloalkyl, perhaloalkyl, haloalkoxy,
perhaloalkoxy, aryl, heterocyclyl, --OH, --OR.sub.7, --CN,
--NO.sub.2, --NR.sub.1R.sub.7, --C(O)R.sub.7,
--C(O)NR.sub.1R.sub.7, --NR.sub.1C(O)R.sub.7, --SR.sub.7,
--S(O)R.sub.7, --S(O).sub.2R.sub.7, --OS(O).sub.2R.sub.7,
--S(O).sub.2NR.sub.1R.sub.7, --NR.sub.1S(O).sub.2R.sub.7,
--(CR.sub.aR.sub.b).sub.mNR.sub.1R.sub.7,
--(CR.sub.aR.sub.b).sub.mO(CR.sub.aR.sub.b).sub.mR.sub.7,
--(CR.sub.aR.sub.b).sub.mNR.sub.1(CR.sub.aR.sub.b).sub.mR.sub.7 or
--(CR.sub.aR.sub.b).sub.mNR.sub.1(CR.sub.aR.sub.b).sub.mCOOR.sub.8.
In certain embodiments, the invention provides compounds of each of
structures I-R/S (49)-(53) where R.sub.3 is alkyl.
In certain embodiments, the invention provides a compound of
Formula I-R and/or Formula I-S where Y.sub.1 and Y.sub.2 are null,
Z is --C(O)-- and B is heterocyclyl or heterocyclylalkyl.
Representative compounds of this embodiment include compounds of
the following structures (wherein "" represents either or both the
R and S form of the compound):
##STR00020## ##STR00021## ##STR00022##
In certain embodiments, the invention provides compounds of each of
structures I-R/S(54)-(66) where W.sub.1 is null.
In certain embodiments, the invention provides compounds of each of
structures I-R/S(54)-(66) where W.sub.1 is null and R.sub.3 is
halo, alkyl, alkyl substituted with R.sub.31, alkoxy, haloalkyl,
perhaloalkyl, haloalkoxy, perhaloalkoxy, aryl, heterocyclyl, --OH,
--OR.sub.7, --CN, --NO.sub.2, --NR.sub.1R.sub.7, --C(O)R.sub.7,
--C(O)NR.sub.1R.sub.7, --NR.sub.1C(O)R.sub.7, --SR.sub.7,
--S(O)R.sub.7, --S(O).sub.2R.sub.7, --OS(O).sub.2R.sub.7,
--S(O).sub.2NR.sub.1R.sub.7, --NR.sub.1S(O).sub.2R.sub.7,
--(CR.sub.aR.sub.b).sub.mNR.sub.1R.sub.7,
--(CR.sub.aR.sub.b).sub.mO(CR.sub.aR.sub.b).sub.mR.sub.7,
--(CR.sub.aR.sub.b).sub.mNR.sub.1(CR.sub.aR.sub.b).sub.mR.sub.7 or
--(CR.sub.aR.sub.b).sub.mNR.sub.1(CR.sub.aR.sub.b).
In certain embodiments, the invention provides compounds of each of
structures I-R/S(54)-(66) where W.sub.1 is null, p is 1 and R.sub.3
is alkyl.
In certain embodiments, the invention provides compounds of each of
structures I-R/S(1)-(66) where R.sub.2 is --OH,
--N(R.sub.1)--(CR.sub.aR.sub.b).sub.m--COOH or
--N(R.sub.1)--SO.sub.2--R.sub.7; where R.sub.1 is H; where R.sub.a
and R.sub.b are independently H, alkyl, alkoxy,
--(CHR.sub.40).sub.mC(O)NR.sub.41R.sub.42,
--(CHR.sub.40).sub.mC(O)OR.sub.40,
--(CHR.sub.40).sub.mNR.sub.41R.sub.42,
--(CHR.sub.40).sub.mSR.sub.40, aryl optionally substituted with
R.sub.7, or wherein R.sub.1 and any one of R.sub.a or R.sub.b taken
together with the carbon(s) to which they are attached form
heterocyclyl; R.sub.8 is alkyl; and m is 1 or 2.
In certain embodiments, the invention provides compounds of the
following structures (wherein "" represents either or both the R
and S form of the compound):
##STR00023## ##STR00024## ##STR00025##
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where A is a 5-membered heteroaryl.
In certain embodiments, the invention provides compounds of
structure I-R/S(57)-(82) where A is a 6-membered heteroaryl.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82)) where A is a 6-membered heteroaryl having
one or two nitrogen atoms.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where A is pyrimindinyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where A is pyridinyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where B is aryl.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where B is phenyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where B is heteroaryl.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where B is thiophenyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where R.sub.2 is --OH.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where R.sub.2 is
--N(R.sub.1)(CR.sub.aR.sub.b).sub.mCOOR.sub.8.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where R.sub.2 is
--N(R.sub.1)SO.sub.2R.sub.7.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where R.sub.2 is --NHCH.sub.2COOH.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where R.sub.2 is --NH(CHR.sub.b)COOH where
R.sub.b is alkyl optionally substituted with R.sub.7,
--(CHR.sub.40).sub.mOR.sub.40, --(CHR.sub.40).sub.mSR.sub.40,
--(CHR.sub.40).sub.mNR.sub.41R.sub.42,
--(CHR.sub.40).sub.mC(O)NR.sub.41R.sub.42,
--(CHR.sub.40).sub.mC(O)N(R.sub.1)(CHR.sub.40).sub.mNR.sub.41R.sub.42,
--(CHR.sub.40).sub.mC(O)N(R.sub.1)(CHR.sub.40).sub.mC(O)NR.sub.41R.sub.42-
, --(CHR.sub.40).sub.mC(O)N(R.sub.1)(CHR.sub.40).sub.mC(O)OR.sub.40
or --(CHR.sub.40)m-S--S--R.sub.40
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where R.sub.2 is
--NH(CR.sub.aR.sub.b).sub.mCOOH where R.sub.a and R.sub.b are
independently H, alkyl optionally substituted with R.sub.7,
--(CHR.sub.40).sub.mOR.sub.40, --(CHR.sub.40).sub.mSR.sub.40,
--(CHR.sub.40).sub.mNR.sub.41R.sub.42,
--(CHR.sub.40).sub.mC(O)NR.sub.41R.sub.42,
--(CHR.sub.40).sub.mC(O)N(R.sub.1)(CHR.sub.40).sub.mNR.sub.41R.sub.42,
--(CHR.sub.40).sub.mC(O)N(R.sub.1)--(CHR.sub.40).sub.mC(O)NR.sub.41R.sub.-
42,
--(CHR.sub.40).sub.mC(O)N(R.sub.1)(CHR.sub.40).sub.mC(O)OR.sub.40
or --(CHR.sub.40)m-S--S--R.sub.40.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where R.sub.2 is
--NR.sub.1(CHR.sub.b).sub.mCOOH where R.sub.1 and R.sub.b taken
together form heterocyclyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where R.sub.2 is
--NR.sub.1(CR.sub.aR.sub.b).sub.mCOOH where R.sub.1 and one of
R.sub.b taken together form heterocyclyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where any two R.sub.a and R.sub.b taken
together with the carbon to which they are attached form a
cycloalkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where R.sub.2 is
--NH(CR.sub.aR.sub.b).sub.mCOOH where one of R.sub.a and R.sub.b is
H and the other R.sub.a and R.sub.b is aryl substituted with
R.sub.7.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where p is 1 or 2 and each R.sub.3 is
independently alkyl, alkoxy, --OH, perhaloalkyl or
--C(O)R.sub.8.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where p is 1 and each R.sub.3 is
alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where q is 1 and R.sub.5 is
--(CR.sub.aR.sub.b).sub.m-L.sub.2-(CR.sub.aR.sub.b).sub.m--R.sub.7,
and in more specific embodiments where q is 1 and R.sub.5 is
--(CH.sub.2).sub.m-L.sub.2-(CH.sub.2).sub.m--R.sub.7.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where q is 1 and R.sub.5 is alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(67)-(82) where q is 1 and R.sub.5 is R.sub.7.
In certain embodiments, the invention provides compounds of each of
structures I-R/S(67)-(82) where q is 1, R.sub.5 is R.sub.7, and
R.sub.7 is halo, alkyl, haloalkyl, perhaloalkyl, alkoxy,
--(CR.sub.aR.sub.b).sub.mOH, --(CR.sub.aR.sub.b).sub.mOR.sub.8,
--(CR.sub.aR.sub.b).sub.mCN,
--(CR.sub.aR.sub.b).sub.mNH(C.dbd.NH)NH.sub.2,
--(CR.sub.aR.sub.b).sub.mNR.sub.1R.sub.8,
--(CR.sub.aR.sub.b).sub.mO(CR.sub.aR.sub.b).sub.mR.sub.8,
--(CR.sub.aR.sub.b).sub.mNR.sub.1(CR.sub.aR.sub.b).sub.mR.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)R.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)OR.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)NR.sub.1R.sub.8,
--(CR.sub.aR.sub.b).sub.mNR.sub.1(CR.sub.aR.sub.b).sub.mC(O)OR.sub.8,
--(CR.sub.aR.sub.b).sub.mNR.sub.1C(O)R.sub.8,
--(CR.sub.aR.sub.b).sub.mC(O)NR.sub.1R.sub.8,
--(CR.sub.aR.sub.b).sub.mSR.sub.8,
--(CR.sub.aR.sub.b).sub.mS(O)R.sub.8,
--(CR.sub.aR.sub.b).sub.mS(O).sub.2R.sub.8,
--(CR.sub.aR.sub.b).sub.mS(O).sub.2NR.sub.1R.sub.8,
--(CR.sub.aR.sub.b).sub.mNR.sub.1S(O).sub.2R.sub.8.
In certain embodiments, the invention provides compounds of each of
structures I-R/S(67)-(82) where q is 1, R.sub.5 is R.sub.7, and
R.sub.7 is a ring moiety selected from cycloalkyl, aryl, aralkyl,
heterocyclyl or heterocyclylalkyl, where such ring moiety is
optionally (singly or multiply) substituted with halo, --OH, --CN,
alkyl, alkoxy, haloalkyl or perhaloalkyl.
In certain embodiments, the invention provides compounds of the
following structures (wherein "" represents either or both the R
and S form of the compound):
##STR00026## wherein C(R.sub.5).sub.q is selected from one of the
following:
##STR00027##
In certain embodiments, the invention provides compounds of
structure I-R/S(83) where B is phenyl or thiophenyl. Representative
compounds of this embodiment include compounds of the following
structure (wherein "" represents either or both the R and S form of
the compound):
##STR00028##
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where p is 1 and R.sub.3 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where p is 1 and R.sub.3 is
tert-butyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where q is 1 and R.sub.5 is alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where q is 1 and R.sub.5 is C.sub.4-8
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where q is 1 and R.sub.5 is C.sub.6-8
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where p is 1, R.sub.3 is tert-butyl, q is
1 and R.sub.5 is C.sub.6-8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where p is 1, R.sub.3 is tert-butyl, q is
1 and R.sub.5 is C.sub.6 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where p is 1, R.sub.3 is tert-butyl, q is
1 and R.sub.5 is C.sub.7 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where q is 1 and R.sub.5 is C.sub.6
alkoxy
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where q is 1 and R.sub.5 is C.sub.7
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where q is 1 and R.sub.5 is C.sub.8
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where q is 1 and R.sub.5 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where q is 1 and R.sub.5 is C.sub.1-4
alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where q is 1 and R.sub.5 is
cycloalkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where q is 1 and R.sub.5 is
cyclopropyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where p is 1, R.sub.3 is alkyl, q is 1 and
R.sub.5 is alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where p is 1, R.sub.3 is tert-butyl, q is
1 and R.sub.5 is C.sub.4-8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where p is 1, R.sub.3 is tert-butyl, q is
1 and R.sub.5 is C.sub.7 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where p is 1, R.sub.3 is tert-butyl, q is
1 and R.sub.5 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where p is 1, R.sub.3 is tert-butyl, q is
1 and R.sub.5 is C.sub.1-4 alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where p is 1, R.sub.3 is tert-butyl, q is
1 and R.sub.5 is cycloalkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where p is 1, R.sub.3 is tert-butyl, q is
1 and R.sub.5 is cyclopropyl.
In certain embodiments, the invention provides compounds of the
following structures (wherein "" represents either or both the R
and S form of the compound):
##STR00029##
In certain embodiments, the invention provides compounds of
structure I-R/S(86) where B is phenyl or thiophenyl. Representative
compounds of this embodiment include compounds of the following
structure (wherein "" represents either or both the R and S form of
the compound):
##STR00030##
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where aralkyl is benzyl
(--CH.sub.2phenyl), phenylethyl (--CH.sub.2CH.sub.2phenyl) or
phenylethylene (--CH.dbd.CHphenyl).
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where aralkyl is benzyl
(--CH.sub.2phenyl).
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where aralkyl is phenylethyl
(--CH.sub.2CH.sub.2phenyl).
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where aralkyl is phenylethylene
(--CH.dbd.CHphenyl).
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where p is 1 and R.sub.3 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where p is 1 and R.sub.3 is
tert-butyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where q is 1 and R.sub.5 is alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where q is 1 and R.sub.5 is C.sub.4-8
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where q is 1 and R.sub.5 is C.sub.6-8
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where q is 1 and R.sub.5 is C.sub.6
alkoxy
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where q is 1 and R.sub.5 is C.sub.7
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where q is 1 and R.sub.5 is C.sub.8
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where q is 1 and R.sub.5 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where q is 1 and R.sub.5 is C.sub.1-4
alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where q is 1 and R.sub.5 is
cycloalkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where q is 1 and R.sub.5 is
cyclopropyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is alkyl, q is 1 and R.sub.5 is
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is C.sub.4-8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is C.sub.6-8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is C.sub.6 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is C.sub.7 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is C.sub.8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where aralkyl is phenylethylene, p is 1,
R.sub.3 is tert-butyl, q is 1 and R.sub.5 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where aralkyl is phenylethylene, p is 1,
R.sub.3 is tert-butyl, q is 1 and R.sub.5 is C.sub.1-4 alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is cycloalkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(87)-(88) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is cyclopropyl.
In certain embodiments, the invention provides compounds of the
following structures (wherein "" represents either or both the R
and S form of the compound):
##STR00031## wherein C is selected from one of the following:
##STR00032##
In certain embodiments, the invention provides compounds the
invention provides compounds of the following structures (wherein
"" represents either or both the R and S form of the compound):
##STR00033##
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where R.sub.1 is hydrogen.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where R.sub.8 is hydrogen.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where m is 2, R.sub.1 is hydrogen, each
occurrence of R.sub.a and R.sub.b are hydrogen, and R.sub.8 is
hydrogen.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where m is 2, a single R.sub.a (i.e., one
of the two) is hydrogen, each occurrence of R.sub.b is hydrogen,
and R.sub.8 is hydrogen.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where m is 1 and R.sub.1, R.sub.a, R.sub.b
and R.sub.8 are hydrogen.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where m is 1, R.sub.a is alkyl and
R.sub.1, R.sub.b and R.sub.8 are hydrogen.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where m is 1, R.sub.a is methyl and
R.sub.1, R.sub.b and R.sub.8 are hydrogen.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where aralkyl is benzyl
(--CH.sub.2phenyl), phenylethyl (--CH.sub.2CH.sub.2phenyl) or
phenylethylene (--CH.dbd.CHphenyl).
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where aralkyl is benzyl
(--CH.sub.2phenyl).
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where aralkyl is phenylethyl
(--CH.sub.2CH.sub.2phenyl).
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where aralkyl is phenylethylene
(--CH.dbd.CHphenyl).
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where p is 1 and R.sub.3 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where p is 1 and R.sub.3 is
tert-butyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where q is 1 and R.sub.5 is alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where q is 1 and R.sub.5 is C.sub.4-8
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where q is 1 and R.sub.5 is C.sub.6-8
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where q is 1 and R.sub.5 is C.sub.6
alkoxy
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where q is 1 and R.sub.5 is C.sub.7
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where q is 1 and R.sub.5 is C.sub.8
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where q is 1 and R.sub.5 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where q is 1 and R.sub.5 is C.sub.1-4
alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where q is 1 and R.sub.5 is
cycloalkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where q is 1 and R.sub.5 is
cyclopropyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(91)-(92) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is alkyl, q is 1 and R.sub.5 is
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(91)-(92) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is C.sub.4-8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(91)-(92) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is C.sub.6-8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(91)-(92) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is C.sub.6 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(91)-(92) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is C.sub.7 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(91)-(92) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is C.sub.8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(91)-(92) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(91)-(92) where aralkyl is phenylethylene, p is 1,
R.sub.3 is tert-butyl, q is 1 and R.sub.5 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(91)-(92) where aralkyl is phenylethylene, p is 1,
R.sub.3 is tert-butyl, q is 1 and R.sub.5 is C.sub.1-4 alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(91)-(92) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is cycloalkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(91)-(92) where aralkyl is benzyl, phenylethyl or
phenylethylene, p is 1, R.sub.3 is tert-butyl, q is 1 and R.sub.5
is cyclopropyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(92) where m is 2, R.sub.1 is hydrogen, each
occurrence of R.sub.a and R.sub.b are hydrogen, and R.sub.8 is
hydrogen. Representative compounds of this embodiment include
compounds of the following structure (wherein "" represents either
or both the R and S form of the compound):
##STR00034##
In certain embodiments, the invention provides compounds of
structure I-R/S(93)-(94) where p is 1 and R.sub.3 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(93)-(94) where p is 1 and R.sub.3 is
tert-butyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(93)-(94) where q is 1 and R.sub.5 is alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(93)-(94) where q is 1 and R.sub.5 is C.sub.4-8
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(93)-(94) where q is 1 and R.sub.5 is C.sub.7
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(93)-(94) where p is 1, R.sub.3 is alkyl, q is 1 and
R.sub.5 is C.sub.4-8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(90) where m is 1 and R.sub.1, R.sub.b and
R.sub.8 are hydrogen. Representative compounds of this embodiment
include compounds of the following structure (wherein "" represents
either or both the R and S form of the compound):
##STR00035##
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(90) where m is 2, a single R.sub.a (i.e., one
of the two) is hydrogen, each occurrence of R.sub.b is hydrogen,
and R.sub.8 is hydrogen. Representative compounds of this
embodiment include compounds of the following structure (wherein ""
represents either or both the R and S form of the compound):
##STR00036##
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is alkyl optionally
substituted with R.sub.7, wherein alkyl includes straight and
branched alkyl groups such as methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl and tert-butyl, as well as cycloalkyl
groups such as cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is methyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is heterocycle or
heterocyclylalkyl, either which may be optionally substituted with
R.sub.7.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is heterocycle, such as
pyrazinyl, pyrimidinyl, pyridazinyl, thiadiazolyl, oxadiazolyl,
imidazolinyl, hexahydropyrimidinyl, diazepanyl, triazinyl,
imidazolyl, pyrrolidinyl, furanyl, tetrahydrofuranyl,
tetrahydro-2H-pyranyl, dioxolanyl, piperidinyl, piperazinyl,
morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,
isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl,
benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl,
azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl,
benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl,
isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,
guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,
quinoxalinyl, and quinazolinyl, any of which may be optionally
substituted with R.sub.7.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is aryl or aralkyl, either
of which may be optionally substituted with R.sub.7.
In certain embodiments, the invention provides compounds of
I-R/S(95)-(98) where R.sub.a is aryl or aralkyl, such as phenyl or
benzyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is aryl or heteroaryl
substituted with R.sub.7.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is phenyl or benzyl
substituted with hydroxyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--CH(OH)C.sub.6H.sub.5.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CHR.sub.40).sub.mC(O)OR.sub.40.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CH.sub.2).sub.mC(O)OH.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CHR.sub.40).sub.mOR.sub.40.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is --(CH.sub.2).sub.mOH.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is --CH.sub.2OH.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CHR.sub.40).sub.mSR.sub.40.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CH.sub.2).sub.mSR.sub.40, where R.sub.40 is H or alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CHR.sub.40).sub.mNR.sub.41R.sub.42.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CH.sub.2).sub.mNR.sub.41R.sub.42.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CHR.sub.40).sub.mC(O)NR.sub.41R.sub.42.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CH.sub.2).sub.mC(O)NR.sub.41R.sub.42.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is --CH.sub.2C(O)NH.sub.2 or
--CH.sub.2CH.sub.2C(O)NH.sub.2
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CHR.sub.40).sub.mC(O)N(R.sub.1)(CHR.sub.40).sub.mNR.sub.41R.sub.42.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CH.sub.2).sub.mC(O)N(R.sub.1)(CH.sub.2).sub.mNR.sub.41R.sub.42.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CHR.sub.40).sub.mC(O)N(R.sub.1)(CHR.sub.40).sub.mC(O)NR.sub.41R.sub.42-
.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CH.sub.2).sub.mC(O)N(R.sub.1)(CH.sub.2).sub.mC(O)NR.sub.41R.sub.42.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CHR.sub.40).sub.mC(O)N(R.sub.1)(CHR.sub.40).sub.mC(O)OR.sub.40.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CH.sub.2).sub.mC(O)N(R.sub.1)(CH.sub.2).sub.mC(O)OR.sub.40.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CHR.sub.40).sub.m--S--S--R.sub.40.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where R.sub.a is
--(CH.sub.2).sub.m--S--S--R.sub.40.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) wherein, within the R.sub.a group,
R.sub.1, R.sub.40, R.sub.41 and R.sub.42 are hydrogen.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) wherein, within the R.sub.a group, m is
1.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) wherein, within the R.sub.a group, m is
2.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where p is 1 and R.sub.3 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where p is 1 and R.sub.3 is
tert-butyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where q is 1 and R.sub.5 is alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where q is 1 and R.sub.5 is C.sub.4-8
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where q is 1 and R.sub.5 is C.sub.7
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(95)-(98) where p is 1, R.sub.3 is alkyl, q is 1 and
R.sub.5 is C.sub.4-8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(90) where m is 1, R.sub.b is hydrogen and
R.sub.1 and R.sub.a taken together with the atoms to which they are
attached form a heterocyclyl optionally substituted (singly or
multiply) with R.sub.7. Representative compounds of this embodiment
include compounds of the following structure (wherein "" represents
either or both the R and S form of the compound):
##STR00037##
In certain embodiments, the invention provides compounds of
structure I-R/S(89)-(90) where m is 2, R.sub.b of the second
(CR.sub.aR.sub.b) group is hydrogen and R.sub.1 and R.sub.a of the
second (CR.sub.aR.sub.b) group taken together with the atoms to
which they are attached form a heterocyclyl optionally substituted
(singly or multiply) with R.sub.7. Representative compounds of this
embodiment include compounds of the following structure (wherein ""
represents either or both the R and S form of the compound):
##STR00038##
In certain embodiments, the invention provides compounds of
structure I-R/S(99)-(102) where R.sub.1 and R.sub.a taken together
with the atoms to which they are attached form azetidinyl,
pyrrolindinyl, piperidinyl optionally substituted (singly or
multiply) with R.sub.7. Representative compounds of this embodiment
include compounds of the following structure (wherein "" represents
either or both the R and S form of the compound):
##STR00039## ##STR00040##
In certain embodiments, the invention provides compounds of
structure I-R/S(99)-(110) where p is 1 and R.sub.3 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(99)-(110) where p is 1 and R.sub.3 is
tert-butyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(99)-(110) where q is 1 and R.sub.5 is alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(99)-(110) where q is 1 and R.sub.5 is C.sub.4-8
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(99)-(110) where q is 1 and R.sub.5 is C.sub.7
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(99)-(110) where p is 1, R.sub.3 is alkyl, q is 1
and R.sub.5 is C.sub.4-8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(99)-(110) where R.sub.7 is absent.
In certain embodiments, the invention provides compounds of
structure I-R/S(99)-(110) where R.sub.7 is hydroxyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(99)-(110) where R.sub.7 is absent, p is 1, R.sub.3
is alkyl, q is 1 and R.sub.5 is C.sub.4-8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(99)-(110) where R.sub.5 is cycloalkyl substituted
with R.sub.10 and q is 1.
In certain embodiments, the invention provides compounds of
structure I-R/S(99)-(110) where R.sub.5 is cycloalkyl substituted
with R.sub.10 and q is 1, where R.sub.10 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(99)-(110) where R.sub.5 is cyclohexyl substituted
with R.sub.10 and q is 1, where R.sub.10 is n-propyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(99)-(110) where R.sub.7 is hydroxyl, p is 1,
R.sub.3 is alkyl, q is 1 and R.sub.5 is C.sub.4-8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where R.sub.2 is
--N(R.sub.1)--SO.sub.2--R.sub.8. Representative compounds of this
embodiment include compounds of the following structure (wherein ""
represents either or both the R and S form of the compound):
##STR00041##
In certain embodiments, the invention provides compounds of
structure I-R/S(111)-(112) where R.sub.1 is hydrogen.
In certain embodiments, the invention provides compounds of
structure I-R/S(111)-(112) where R.sub.1 is hydrogen an R.sub.8 is
alkyl optionally substituted (singly or multiply) with R.sub.7.
In certain embodiments, the invention provides compounds of
structure I-R/S(111)-(114) where R.sub.1 is hydrogen an R.sub.8 is
alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(111)-(112) where R.sub.1 is hydrogen an R.sub.8 is
methyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(111)-(112) where p is 1 and R.sub.3 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(111)-(112) where p is 1 and R.sub.3 is
tert-butyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(111)-(112) where q is 1 and R.sub.5 is alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(111)-(112) where q is 1 and R.sub.5 is C.sub.4-8
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(111)-(112) where q is 1 and R.sub.5 is C.sub.7
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(111)-(112) where p is 1, R.sub.3 is alkyl, q is 1
and R.sub.5 is C.sub.4-8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(111)-(112) where R.sub.5 is cycloalkyl substituted
with R.sub.10 and q is 1.
In certain embodiments, the invention provides compounds of
structure I-R/S(111)-(112) where R.sub.5 is cycloalkyl substituted
with R.sub.10 and q is 1, where R.sub.10 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(111)-(112) where R.sub.5 is cyclohexyl substituted
with R.sub.10 and q is 1, where R.sub.10 is n-propyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where R.sub.2 is --OH. Representative
compounds of this embodiment include compounds of the following
structure (wherein "" represents either or both the R and S form of
the compound):
##STR00042##
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where R.sub.2 is --N(R.sub.1)(R.sub.42).
Representative compounds of this embodiment include compounds of
the following structure (wherein "" represents either or both the R
and S form of the compound):
##STR00043##
In certain embodiments, the invention provides compounds of
structure I-R/S(115)-(116) where R.sub.41 and R.sub.42 are
independently R.sub.40, --(CHR.sub.40).sub.n--C(O)OR.sub.40,
--(CHR.sub.40).sub.n--C(O)R.sub.40,
--(CH.sub.2).sub.nN(R.sub.1)(R.sub.7), aryl or heteroaryl, which
aryl or heteroaryl is optionally substituted (singly or multiply)
with R.sub.7.
In certain embodiments, the invention provides compounds of
structure I-R/S(115)-(116) where R.sub.41 is hydrogen and R.sub.42
is alkyl optionally substituted (singly or multiply) with
R.sub.7.
In certain embodiments, the invention provides compounds of
structure I-R/S(115)-(116) where R.sub.41 is hydrogen and R.sub.42
is --(CHR.sub.40).sub.nC(O)OR.sub.40.
In certain embodiments, the invention provides compounds of
structure I-R/S(115)-(116) where R.sub.41 is hydrogen and R.sub.42
is --(CHR.sub.40).sub.nC(O)R.sub.40.
In certain embodiments, the invention provides compounds of
structure I-R/S(115)-(116) where R.sub.41 is hydrogen and R.sub.42
is --(CH.sub.2).sub.nN(R.sub.1)(R.sub.7).
In certain embodiments, the invention provides compounds of
structure I-R/S(115)-(116) where R.sub.41 is hydrogen and R.sub.42
is aryl optionally substituted (singly or multiply) with
R.sub.7.
In certain embodiments, the invention provides compounds of
structure I-R/S(115)-(116) where R.sub.41 is hydrogen and R.sub.42
is heteroaryl optionally substituted (singly or multiply) with
R.sub.7.
In certain embodiments, the invention provides compounds of
structure I-R/S(115)-(116) where R.sub.41 and R.sub.42 taken
together with the N atom to which they are attached form a 3- to
7-membered heterocyclyl optionally substituted (singly or multiply)
with R.sub.7.
In certain embodiments, the invention provides compounds of
structure I-R/S(115)-(116) where R.sub.41 and R.sub.42 taken
together with the N atom to which they are attached form pyrazinyl,
pyrimidinyl, pyridazinyl, thiadiazolyl, oxadiazolyl, imidazolinyl,
hexahydropyrimidinyl, diazepanyl, triazinyl, imidazolyl,
pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl,
pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl
or pyridinyl, any of which may be optionally substituted (singly or
multiply) with R.sub.7.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where R.sub.2 is
--N(R.sub.1)(CR.sub.aR.sub.b).sub.mCON(R.sub.1)(R.sub.40).
Representative compounds of this embodiment include compounds of
the following structure (wherein "" represents either or both the R
and S form of the compound):
##STR00044##
In certain embodiments, the invention provides compounds of
structure I-R/S( )-(118) where m is 1, R.sub.b is hydrogen and
R.sub.1 and R.sub.a taken together with the atoms to which they are
attached form a heterocyclyl optionally substituted (singly or
multiply) with R.sub.7. Representative compounds of this embodiment
include compounds of the following structure (wherein "" represents
either or both the R and S form of the compound):
##STR00045##
In certain embodiments, the invention provides compounds of
structure I-R/S(117)-(118) where m is 2, R.sub.b of the second
(CR.sub.aR.sub.b) group is hydrogen and R.sub.1 and R.sub.a of the
second (CR.sub.aR.sub.b) group taken together with the atoms to
which they are attached form a heterocyclyl optionally substituted
(singly or multiply) with R.sub.7. Representative compounds of this
embodiment include compounds of the following structure (wherein ""
represents either or both the R and S form of the compound):
##STR00046##
In certain embodiments, the invention provides compounds of
structure I-R/S(119)-(122) where R.sub.1 and R.sub.a taken together
with the atoms to which they are attached form azetidinyl,
pyrrolindinyl, piperidinyl optionally substituted (singly or
multiply) with R.sub.7. Representative compounds of this embodiment
include compounds of the following structure (wherein "" represents
either or both the R and S form of the compound):
##STR00047## ##STR00048##
In certain embodiments, the invention provides compounds of
structure I-R/S(117)-(128) where p is 1 and R.sub.3 is alkyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(117)-(128) where p is 1 and R.sub.3 is
tert-butyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(117)-(128) where q is 1 and R.sub.5 is alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(117)-(128) where q is 1 and R.sub.5 is C.sub.4-8
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(117)-(128) where q is 1 and R.sub.5 is C.sub.7
alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(117)-(128) where p is 1, R.sub.3 is alkyl, q is 1
and R.sub.5 is C.sub.4-8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(117)-(128) where R.sub.7 is absent or hydroxyl.
In certain embodiments, the invention provides compounds of
structure I-R/S(117)-(128) where R.sub.7 is absent or hydroxyl, p
is 1, R.sub.3 is alkyl, q is 1 and R.sub.5 is C.sub.4-8 alkoxy.
In certain embodiments, the invention provides compounds of
structure I-R/S(117)-(128) where R.sub.1 is hydrogen.
In certain embodiments, the invention provides compounds of
structure I-R/S(117)-(128) where R.sub.40 is R.sub.7.
In certain embodiments, the invention provides compounds of
structure I-R/S(117)-(128) where R.sub.40 is R.sub.7, R.sub.7 is
--(CR.sub.aR.sub.b).sub.mS(O).sub.2R.sub.8, and R.sub.8 is
--(CR.sub.aR.sub.b).sub.m-L.sub.2-(CR.sub.aR.sub.b).sub.m--R.sub.1.
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where R.sub.2 is
--N(R.sub.1)(CR.sub.aR.sub.b).sub.mN(R.sub.1)C(O)O(R.sub.8).
Representative compounds of this embodiment include compounds of
the following structure (wherein "" represents either or both the R
and S form of the compound):
##STR00049##
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where R.sub.2 is
--N(R.sub.1)(CR.sub.aR.sub.b).sub.mN(R.sub.1)(R.sub.7).
Representative compounds of this embodiment include compounds of
the following structure (wherein "" represents either or both the R
and S form of the compound):
##STR00050##
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where R.sub.2 is
--N(R.sub.1)(CR.sub.aR.sub.b).sub.mCON(R.sub.1)heterocyclyl.
Representative compounds of this embodiment include compounds of
the following structure (wherein "" represents either or both the R
and S form of the compound):
##STR00051##
In certain embodiments, the invention provides compounds of
structure I-R/S(84)-(85) where R.sub.2 is
--N(R.sub.1)(CR.sub.aR.sub.b).sub.m-heterocyclyl, which
heterocyclyl may be optionally substituted with R.sub.7.
Representative compounds of this embodiment include compounds of
the following structure (wherein "" represents either or both the R
and S form of the compound):
##STR00052##
In certain embodiments, the invention provides compounds of
structures I-R/S(87)-(88) where R.sub.2 is as shown in each of
structures I-R/S(91) through I-R/S(136). For example, structures
I-R/S(91)-(92) depict structures I-R/S(87)-(88) when R.sub.2 is
--N(R.sub.1)(CR.sub.aR.sub.b).sub.mCOOR.sub.8. In a similar manner,
the R.sub.2 groups shown in each of structures I-R/S(93) through
I-R/S(136) may serve as the R.sub.2 group of structures
I-R/S(87)-(88).
In certain embodiments, the invention provides a compound of
Formula I-R and/or Formula I-S where Y.sub.1 and Y.sub.2 are null
and Z is --S(O).sub.2--. Representative compounds of this
embodiment include compounds of the following structures (wherein
"" represents either or both the R and S form of the compound):
##STR00053##
In certain embodiments, the invention provides compounds of
structure I-R/S(137) where A is pyrimidinyl, B is phenyl and C is
phenyl. Representative compounds of this embodiment include
compounds of the following structure (wherein "" represents either
or both the R and S form of the compound):
##STR00054##
In certain embodiments, the invention provides a compound of
Formula I-R and/or Formula I-S where Y.sub.1 is null, Y.sub.2 is
--O-- and Z is --C(O)--. Representative compounds of this
embodiment include compounds of the following structures (wherein
"" represents either or both the R and S form of the compound):
##STR00055##
In certain embodiments, the invention provides a compound of
Formula I-R and/or Formula I-S where Y.sub.1 is NH, Y.sub.2 is null
and Z is --C(O)--. Representative compounds of this embodiment
include compounds of the following structures (wherein ""
represents either or both the R and S form of the compound):
##STR00056##
In certain embodiments, the invention provides a compound of
Formula I-R and/or Formula I-S where C is aryl and A and C are
taken together to form a fused bicyclic ring system between the 5-,
6- or 7-membered heterocyclyl of A and the aryl of C.
Representative compounds of this embodiment include compounds of
the following structures (wherein "" represents either or both the
R and S form of the compound):
##STR00057##
In certain embodiments, the invention provides compounds of
structure I-R/S(141) where Y.sub.1 is null and Z is --C(O)--.
Representative compounds of this embodiment include compounds of
the following structures where one or both of X.sub.A and X.sub.B
is nitrogen (wherein "" represents either or both the R and S form
of the compound):
##STR00058##
In certain embodiments, the invention provides compounds of
structures I-R/S and I-R/S(1)-(29), (49)-(66), (84)-(85),
(93)-(137) and (139)-(140) wherein C is:
##STR00059##
In certain embodiments, the invention provides compounds of
structures I-R/S and I-R/S(1)-(29), (49)-(66), (84)-(85),
(93)-(137) and (139)-(140) wherein C is:
##STR00060##
In certain embodiments, the invention provides compounds of
structures I-R/S and I-R/S(1)-(29), (49)-(66), (84)-(85),
(93)-(137) and (139)-(140) wherein C is:
##STR00061##
In certain embodiments, the invention provides compounds of
structures I-R/S and I-R/S(1)-(29), (49)-(66), (84)-(85),
(93)-(137) and (139)-(140) wherein C is:
##STR00062##
In certain embodiments, the invention provides compounds of
structures I-R/S and I-R/S(1)-(29), (49)-(66), (84)-(85),
(93)-(137) and (139)-(140) wherein C is:
##STR00063##
In certain embodiments, the invention provides compounds of
structures I-R/S and I-R/S(1)-(29), (49)-(66), (84)-(85),
(93)-(137) and (139)-(140) wherein C is:
##STR00064##
In certain embodiments, the invention provides compounds of
structures I-R/S and I-R/S(1)-(29), (49)-(66), (84)-(85),
(93)-(137) and (139)-(140) wherein C is:
##STR00065##
In certain embodiments, the invention provides compounds of
structures I-R/S and I-R/S(1)-(29), (49)-(66), (84)-(85),
(93)-(137) and (139)-(140) wherein C is:
##STR00066##
In certain embodiments, the invention provides compounds of
structures I-R/S and I-R/S(1)-(29), (49)-(66), (84)-(85),
(93)-(137) and (139)-(140) wherein C is:
##STR00067##
In certain embodiments, the invention provides compounds of
structures I-R/S and I-R/S(1)-(29), (49)-(66), (84)-(85),
(93)-(137) and (139)-(140) wherein C is:
##STR00068##
In certain embodiments, the invention provides compounds of
structures I-R/S and I-R/S(1)-(29), (49)-(66), (84)-(85),
(93)-(137) and (139)-(140) wherein C is:
##STR00069##
In certain embodiments, the invention provides compounds of
structures I-R/S and I-R/S(1)-(29), (49)-(66), (84)-(85),
(93)-(137) and (139)-(140) wherein C is:
##STR00070##
In certain embodiments, the invention provides compounds of
structures I-R/S and I-R/S(1)-(29), (49)-(66), (84)-(85),
(93)-(137) and (139)-(140) wherein C is:
##STR00071##
In certain embodiments, the invention provides compounds of
structures I-R/S and I-R/S(1)-(29), (49)-(66), (84)-(85),
(93)-(137) and (139)-(140) wherein C is:
##STR00072##
In certain embodiments, the invention provides compounds of
structures I-R/S and I-R/S(1)-(29), (49)-(66), (84)-(85),
(93)-(137) and (139)-(140) wherein C is:
##STR00073##
In certain embodiments, the invention provides a pharmaceutical
composition comprising a compound of the invention together with at
least one pharmaceutically acceptable carrier, diluent or
excipient.
In certain embodiments, the invention provides a pharmaceutical
composition comprising a compound of the invention and a second
medicament. In certain of such embodiments, the second medicament
is a GLP-1 agonist or a DPPIV inhibitor.
In certain embodiments, the invention provides a method of use of
compounds of the invention for preparation of a medicament.
In certain embodiments, the invention provides a pharmaceutical
combination comprising a compound of the invention and a second
medicament. In various such embodiments, the second medicament is
an agonist, antagonist, or modulator for glucagon receptor, GIP
receptor, GLP-2 receptor, or PTH receptor, or glucagon-like peptide
1 (GLP-1) receptor. In various such embodiments, the second
medicament is exenatide, liraglutide, taspoglutide, albiglutide, or
lixisenatide or other insulin regulating petptide. In various such
embodiments, the second medicament is a DPPIV inhibitor, such as
sitagliptin. In various such embodiments, the second medicament is
medically indicated for the treatment of type II diabetes. In
various combinations, the second medicament is a sodium-glucose
co-transporter (SGLT) inhibitor, such as a SGLT1 and/or SGLT2
inhibitor, such as dapagliflozin, empagliflozin and canagliflozin.
In various such embodiments, the second medicament is a biguanide
such as metformin, a sulfonylurea such as glibenclamide, glipizide,
gliclazide, and glimepiride, a meglitinide such as repaglinide and
mateglinide, a thiazolidinedione such as pioglitazone and
rosiglitazone, an .alpha.-glucosidase inhibitor such as acarbose
and miglitol, a bile acid sequestrant such as colesevelam, and/or a
dopamine-2 agonist such as bromocriptine.
In certain embodiments, the invention provides a pharmaceutical
composition comprising a compound of the invention and a second
medicament, wherein the second medicament is metformin.
In certain embodiments, the invention provides a pharmaceutical
composition comprising a compound of the invention and a second
medicament, wherein the second medicament is sitagliptin.
In certain embodiments, the invention provides a pharmaceutical
composition comprising a compound of the invention and a second
medicament, wherein the second medicament is dapagliflozin,
empagliflozin or canagliflozin.
In certain embodiments, a method is provided for activation,
potentiation or agonism of a glucagon-like peptide 1 comprising
contacting the receptor with an effective amount of a compound,
pharmaceutical composition or pharmaceutical combination of the
invention.
In further embodiments, a method is provided for activation or
agonism of a GLP-1 receptor by contacting the receptor with an
effective amount of an invention compound and GLP-1 peptides
GLP-1(9-36) and GLP-1(7-36), pharmaceutical composition or
pharmaceutical combination, wherein the GLP-1 receptor is disposed
within a living mammal; in certain embodiments wherein such mammal
is a human.
In certain embodiments, a method is provided for treatment of a
malcondition in a subject for which activation, potentiation or
agonism of a GLP-1 receptor is medically indicated, by
administering an effective amount of an invention compound to the
subject at a frequency and for a duration of time sufficient to
provide a beneficial effect to the patient. In yet further
embodiments, a method is provided for treatment of a malcondition
in a patient for which activation, potentiation, or agonism of a
GLP-1 receptor is medically indicated, by administering an
effective amount of an invention compound to the patient at a
frequency and for a duration of time sufficient to provide a
beneficial effect to the patient, wherein the malcondition
comprises type I diabetes, type II diabetes, gestational diabetes,
obesity, excessive appetite, insufficient satiety, or metabolic
disorder. In certain embodiments, the subject is a patient or a
human being. In certain embodiments, the human being is afflicted
with, or at risk of developing, a disease or condition selected
from the group consisting of type I diabetes, type II diabetes,
gestational diabetes, obesity, excessive appetite, insufficient
satiety, and metabolic disorder. In certain of such embodiments,
said disease is type I diabetes or type II diabetes.
In certain embodiments, the invention provides methods for
synthesis of certain compounds including compounds of the invention
as more fully illustrated herein. In certain other embodiments, the
invention provides certain intermediate compounds associated with
such methods of synthesis as illustrated herein.
In certain embodiments, methods are provided for use of an
invention compound for preparation of a medicament adapted for
treatment of a disorder or a malcondition wherein activation or
inhibition of a GLP-1 receptor is medically indicated. In certain
embodiments, the malcondition comprises type I diabetes, type II
diabetes, gestational diabetes, obesity, excessive appetite,
insufficient satiety, and metabolic disorder. Preferably said
disease is type I diabetes or type II diabetes. In other
embodiments, the malcondition is non-alcoholic fatty liver disease
(NAFLD) and/or non-alcoholic steatohepatitis (NASH).
In certain embodiments, the method additionally comprises
administering to the subject a second medicament selected from the
group of biguanides, peptidic GLP-1 agonists and DPPIV inhibitors,
wherein such second medicament is either a component of the
pharmaceutical composition or a second pharmaceutical composition.
In certain of such embodiments, the second medicament can be
metformin, exenatide or sitagliptin.
As used in the specification and the appended claims, the singular
forms "a," "an" and "the" include plural referents unless the
context clearly dictates otherwise.
As used herein, "individual" (as in the subject of the treatment)
means both mammals and non-mammals. Mammals include, for example,
humans; non-human primates, e.g., apes and monkeys; cattle; horses;
sheep; and goats. Non-mammals include, for example, fish and
birds.
A "receptor", as is well known in the art, is a biomolecular entity
usually comprising a protein that specifically binds a structural
class of ligands or a single native ligand in a living organism,
the binding of which causes the receptor to transduce the binding
signal into another kind of biological action, such as signaling a
cell that a binding event has occurred, which causes the cell to
alter its function in some manner. An example of transduction is
receptor binding of a ligand causing alteration of the activity of
a "G-protein" in the cytoplasm of a living cell. Any molecule,
naturally occurring or not, that binds to a receptor and activates
it for signal transduction, is referred to as an "agonist" or
"activator." Any molecule, naturally occurring or not, that binds
to a receptor, but does not cause signal transduction to occur, and
which can block the binding of an agonist and its consequent signal
transduction, is referred to as an "antagonist." Certain molecules
bind to receptors at locations other than the binding sites of
their natural ligands and such allosteric binding molecules may
potentiate, activate or agonize the receptor and may enhance the
effect of a natural ligand or a co-administered ligand.
A "GLP-1 compound" or "GLP-1 agonist" or "GLP-1 activator" or
"GLP-1 inhibitor" or "GLP-1 antagonist" or "GLP-1 potentiator" or
"GLP-1 modulator" as the terms are used herein refer to compounds
that interact in some way with the GLP-1 receptor. They can be
agonists, potentiators, or activators, or they can be antagonists
or inhibitors. A "GLP-1 compound" of the invention can be selective
for action of the GLP-1 receptor family.
"Substantially" as the term is used herein means completely or
almost completely; for example, a composition that is
"substantially free" of a component either has none of the
component or contains such a trace amount that any relevant
functional property of the composition is unaffected by the
presence of the trace amount, or a compound is "substantially pure"
is there are only negligible traces of impurities present.
Substantially enantiomerically or diastereomerically pure means a
level of enantiomeric or diastereomeric enrichment of one
enantiomer with respect to the other enantiomer or diastereomer of
at least about 80%, and more preferably in excess of 80%, 85%, 90%,
95%, 98%, 99%, 99.5% or 99.9%.
"Treating" or "treatment" within the meaning herein refers to an
alleviation of symptoms associated with a disorder or disease, or
inhibition of further progression or worsening of those symptoms,
or prevention or prophylaxis of the disease or disorder.
The expression "effective amount", when used to describe use of a
compound of the invention in providing therapy to a patient
suffering from a disorder or malcondition mediated by GLP-1 refers
to the amount of a compound of the invention that is effective to
bind to as an agonist or as an antagonist a GLP-1 receptor in the
individual's tissues, wherein the GLP-1 is implicated in the
disorder, wherein such binding occurs to an extent sufficient to
produce a beneficial therapeutic effect on the patient. Similarly,
as used herein, an "effective amount" or a "therapeutically
effective amount" of a compound of the invention refers to an
amount of the compound that alleviates, in whole or in part,
symptoms associated with the disorder or condition, or halts or
slows further progression or worsening of those symptoms, or
prevents or provides prophylaxis for the disorder or condition. In
particular, a "therapeutically effective amount" refers to an
amount effective, at dosages and for periods of time necessary, to
achieve the desired therapeutic result by acting as an agonist of
GLP-1 activity. A therapeutically effective amount is also one in
which any toxic or detrimental effects of compounds of the
invention are outweighed by the therapeutically beneficial effects.
For example, in the context of treating a malcondition mediated by
activation of a GLP-1 receptor, a therapeutically effective amount
of a GLP-1 receptor agonist of the invention is an amount
sufficient to control the malcondition, to mitigate the progress of
the malcondition, or to relieve the symptoms of the malcondition.
Examples of malconditions that can be so treated include, but not
limited to, type II diabetes, as well as NAFLD and NASH.
All chiral, diastereomeric, racemic forms of a structure are
intended, unless a particular stereochemistry or isomeric form is
specifically indicated. Compounds used in the present invention can
include enriched or resolved optical isomers at any or all
asymmetric atoms as are apparent from the depictions, at any degree
of enrichment. Both racemic and diastereomeric mixtures, as well as
the individual optical isomers can be synthesized so as to be
substantially free of their enantiomeric or diastereomeric
partners, and these are all within the scope of certain embodiments
of the invention.
The isomers resulting from the presence of a chiral center comprise
a pair of non-superimposable isomers that are called "enantiomers."
Single enantiomers of a pure compound are optically active, i.e.,
they are capable of rotating the plane of plane polarized light.
Single enantiomers are designated according to the
Cahn-Ingold-Prelog system. Once the priority ranking of the four
groups is determined, the molecule is oriented so that the lowest
ranking group is pointed away from the viewer. Then, if the
descending rank order of the other groups proceeds clockwise, the
molecule is designated (R) and if the descending rank of the other
groups proceeds counterclockwise, the molecule is designated (S).
In the example in Scheme 14, the Cahn-Ingold-Prelog ranking is
A>B>C>D. The lowest ranking atom, D is oriented away from
the viewer.
##STR00074##
"Isolated optical isomer" means a compound which has been
substantially purified from the corresponding optical isomer(s) of
the same formula. Preferably, the isolated isomer is at least about
80%, and preferably at least 80% or even at least 85% pure. In
other embodiments, the isolated isomer is at least 90% pure or at
least 98% pure, or at least about 99% pure, by weight.
Enantiomers are sometimes called optical isomers because a pure
enantiomer rotates plane-polarized light in a particular direction.
If the light rotates clockwise, then that enantiomer is labeled
"(+)" or "d" for dextrorotatory, its counterpart will rotate the
light counterclockwise and is labeled "(-)" or "1" for
levorotatory.
The terms "racemate" and "racemic mixture" are frequently used
interchangeably. A racemate is an equal mixture of two enantiomers.
A racemate is labeled "(.+-.)" because it is not optically active
(i.e., will not rotate plane-polarized light in either direction
since its constituent enantiomers cancel each other out).
It is understood that due to chemical properties (i.e., resonance
lending some double bond character to the C--N bond) of restricted
rotation about the amide bond linkage (as illustrated below) it is
possible to observe separate rotamer species and even, under some
circumstances, to isolate such species, example shown below. It is
further understood that certain structural elements, including
steric bulk or substituents on the amide nitrogen, may enhance the
stability of a rotamer to the extent that a compound may be
isolated as, and exist indefinitely, as a single stable rotamer.
The present invention therefore includes any possible stable
rotamers of compounds of the invention which are biologically
active in the treatment of type I diabetes, type II diabetes,
gestational diabetes, obesity, excessive appetite, insufficient
satiety, metabolic disorder, non-alcoholic fatty liver disease
and/or non-alcoholic steatohepatitis.
##STR00075##
The preferred compounds of the present invention have a particular
spatial arrangement of substituents on the aromatic rings, which
are related to the structure activity relationship demonstrated by
the compound class. Often such substitution arrangement is denoted
by a numbering system; however, numbering systems are often not
consistent between different ring systems. In six-membered aromatic
systems, the spatial arrangements are specified by the common
nomenclature "para" for 1,4-substitution, "meta" for
1,3-substitution and "ortho" for 1,2-substitution as shown
below.
##STR00076##
All structures encompassed within a claim are "chemically
feasible", by which is meant that the structure depicted by any
combination or subcombination of optional substituents meant to be
recited by the claim is physically capable of existence with at
least some stability as can be determined by the laws of structural
chemistry and by experimentation. Structures that are not
chemically feasible are not within a claimed set of compounds.
Further, isotopes of the atoms depicted (such as deuterium and
tritium in the case of hydrogen) are encompassed within the scope
of this invention. For example, it should be understood that
depiction herein of compounds having one or more hydrogen atoms is
intended to encompass compounds having such hydrogen atoms replaced
with deuterium (or tritium) at one or more locations of such
compounds. Such "deuterated compounds", whether partial (i.e, less
than all the hydrogen atoms replaced with deuterium) or complete
(i.e., all the hydrogen atoms replaced with deuterium) is within
the scope of the compounds of this invention.
In general, "substituted" refers to an organic group as defined
herein in which one or more bonds to a hydrogen atom contained
therein are replaced by one or more bonds to a non-hydrogen atom
such as, but not limited to, a halogen (i.e., F, Cl, Br, and I); an
oxygen atom in groups such as hydroxyl groups, alkoxy groups,
aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl
groups including carboxylic acids, carboxylates, and carboyxlate
esters; a sulfur atom in groups such as thiol groups, alkyl and
aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl
groups, and sulfonamide groups; a nitrogen atom in groups such as
amines, hydroxylamines, nitriles, nitro groups, N-oxides,
hydrazides, azides, and enamines; and other heteroatoms in various
other groups. Non-limiting examples of substituents that can be
bonded to a substituted carbon (or other) atom include F, Cl, Br,
I, OR', OC(O)N(R').sub.2, CN, CF.sub.3, OCF.sub.3, R', O, S, C(O),
S(O), methylenedioxy, ethylenedioxy, N(R').sub.2, SR', SOR',
SO.sub.2R', SO.sub.2N(R').sub.2, SO.sub.3R', C(O)R', C(O)C(O)R',
C(O)CH.sub.2C(O)R', C(S)R', C(O)OR', OC(O)R', C(O)N(R').sub.2,
OC(O)N(R').sub.2, C(S)N(R').sub.2, (CH.sub.2).sub.0-2NHC(O)R',
(CH.sub.2).sub.0-2N(R')N(R').sub.2, N(R')N(R')C(O)R',
N(R')N(R')C(O)OR', N(R')N(R')CON(R').sub.2, N(R')SO.sub.2R',
N(R')SO.sub.2N(R').sub.2, N(R')C(O)OR', N(R')C(O)R', N(R')C(S)R',
N(R')C(O)N(R').sub.2, N(R')C(S)N(R').sub.2, N(COR')COR', N(OR')R',
C(.dbd.NH)N(R').sub.2, C(O)N(OR')R', or C(.dbd.NOR')R' wherein R'
can be hydrogen or a carbon-based moiety, and wherein the
carbon-based moiety can itself be further substituted.
Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl
groups as well as other substituted groups also include groups in
which one or more bonds to a hydrogen atom are replaced by one or
more bonds, including double or triple bonds, to a carbon atom, or
to a heteroatom such as, but not limited to, oxygen in carbonyl
(oxo), carboxyl, ester, amide, imide, urethane, and urea groups;
and nitrogen in imines, hydroxyimines, oximes, hydrazones,
amidines, guanidines, and nitriles.
Substituted ring groups include substituted aryl, heterocyclyl and
heteroaryl groups. Substituted ring groups can be substituted by
one or more substituents at any available ring position. In some
embodiments, two substituents on a substituted ring group may taken
together with the ring to which they are attached to form a ring,
such that the two rings are fused together. For example,
benzodioxolyl is a fused ring system formed by two substituents
taken together on a phenyl group.
Such substituted ring groups also include rings and fused ring
systems in which a bond to a hydrogen atom is replaced with a bond
to a carbon atom. Therefore, substituted aryl, heterocyclyl and
heteroaryl groups can also be substituted with alkyl, alkenyl,
cycloalkyl, aryl, heteroaryl, and alkynyl groups as defined herein,
which can themselves be further substituted.
The linking groups (e.g., L.sub.1 and L.sub.2) of Formula I-R or
I-S are partial structures which may be represented by a formula,
say, for example, --N(R.sub.1)--C(O)--, which is read from
left-to-right. Accordingly, the nitrogen atom of the
--N(R.sub.1)--C(O)-- linker will be attached to the proximal end of
the structure of Formula I-R or I-S, and the carbonyl carbon atom
of the --N(R.sub.1)--C(O)-- linker will be attached to the distal
end of the structure of Formula I-R or I-S.
The term "heteroatoms" as used herein refers to non-carbon and
non-hydrogen atoms, capable of forming covalent bonds with carbon,
and is not otherwise limited. Typical heteroatoms are N, O, and S.
When sulfur (S) is referred to, it is understood that the sulfur
can be in any of the oxidation states in which it is found, thus
including sulfoxides (R--S(O)--R') and sulfones
(R--S(O).sub.2--R'), unless the oxidation state is specified; thus,
the term "sulfone" encompasses only the sulfone form of sulfur; the
term "sulfide" encompasses only the sulfide (R--S--R') form of
sulfur. When the phrases such as "heteroatoms selected from the
group consisting of O, NH, NR' and S," or "[variable] is O, S . . .
" are used, they are understood to encompass all of the sulfide,
sulfoxide and sulfone oxidation states of sulfur.
Alkyl groups include straight chain and branched alkyl groups and
cycloalkyl groups having from 1 to about 20 carbon atoms, and
typically from 1 to 12 carbons (C.sub.1-C.sub.12 alkyl), or, in
some embodiments, from 1 to 8 carbon atoms (C.sub.1-C.sub.8 alkyl),
or, in some embodiments, from 1 to 4 carbon atoms (C.sub.1-C.sub.4
alkyl). In the case of cycloalkyl groups, such groups have from
3-20 carbon atoms. Examples of straight chain alkyl groups include,
but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl,
n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl
groups include, but are not limited to, isopropyl, iso-butyl,
sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl
groups. Alkyl groups as used herein may optionally include one or
more further substituent groups. Representative substituted alkyl
groups can be substituted one or more times with any of the groups
listed above, for example, amino, hydroxy, cyano, carboxy, nitro,
thio, alkoxy, and halogen groups.
Cycloalkyl groups are alkyl groups forming a ring structure, which
can be substituted or unsubstituted, wherein the ring is either
completely saturated, partially unsaturated, or fully unsaturated,
wherein if there is unsaturation, the conjugation of the
pi-electrons in the ring do not give rise to aromaticity. Examples
of cycloalkyl include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl
groups. In some embodiments, the cycloalkyl group has 3 to 8 ring
members, whereas in other embodiments the number of ring carbon
atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups
further include polycyclic cycloalkyl groups such as, but not
limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl,
and carenyl groups, and fused rings such as, but not limited to,
decalinyl, and the like. Cycloalkyl groups also include rings that
are substituted with straight or branched chain alkyl groups as
defined above. Representative substituted cycloalkyl groups can be
mono-substituted or substituted one or more times with any of the
groups listed above, for example, but not limited to, amino,
hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen
groups.
The terms "carbocyclic" and "carbocycle" denote a ring structure
wherein the atoms of the ring are carbon. In some embodiments, the
carbocycle has 3 to 8 ring members, whereas in other embodiments
the number of ring carbon atoms is 4, 5, 6, or 7. Unless
specifically indicated to the contrary, the carbocyclic ring can be
substituted with as many as N substituents wherein N is the size of
the carbocyclic ring with for example, amino, hydroxy, cyano,
carboxy, nitro, thio, alkoxy, and halogen groups.
(Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are alkyl
groups as defined above in which a hydrogen or carbon bond of the
alkyl group is replaced with a bond to a cycloalkyl group as
defined above.
Alkenyl groups include straight and branched chain and cyclic alkyl
groups as defined above, except that at least one double bond
exists between two carbon atoms. Thus, alkenyl groups have from 2
to about 20 carbon atoms, and typically from 2 to 12 carbons or, in
some embodiments, from 2 to 8 carbon atoms. Examples include, but
are not limited to --CH.dbd.CH.sub.2, --CH.dbd.CH(CH.sub.3),
--CH.dbd.C(CH.sub.3).sub.2, --C(CH.sub.3).dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH(CH.sub.3), --C(CH.sub.2CH.sub.3).dbd.CH.sub.2,
--CH.dbd.CHCH.sub.2CH.sub.3, --CH.dbd.CH(CH.sub.2).sub.2CH.sub.3,
--CH.dbd.CH(CH.sub.2).sub.3CH.sub.3,
--CH.dbd.CH(CH.sub.2).sub.4CH.sub.3, vinyl, cyclohexenyl,
cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and
hexadienyl among others.
The term "cycloalkenyl" alone or in combination denotes a cyclic
alkenyl group wherein at least one double bond is present in the
ring structure. Cycloalkenyl groups include cycloalkyl groups
having at least one double bond between two adjacent carbon atoms.
Thus for example, cycloalkenyl groups include but are not limited
to cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups, as well
as polycyclic and/or bridging ring systmes such as adamantine.
(Cycloalkenyl)alkyl groups are alkyl groups as defined above in
which a hydrogen or carbon bond of the alkyl group is replaced with
a bond to a cycloalkenyl group as defined above.
Alkynyl groups include straight and branched chain alkyl groups,
except that at least one triple bond exists between two carbon
atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms,
and typically from 2 to 12 carbons or, in some embodiments, from 2
to 8 carbon atoms. Examples include, but are not limited to
--C.ident.CH, --C.ident.C(CH.sub.3), --C.ident.C(CH.sub.2CH.sub.3),
--CH.sub.2C.ident.CH, --CH.sub.2C.ident.C(CH.sub.3), and
--CH.sub.2C.ident.C(CH.sub.2CH.sub.3), among others.
Aryl groups are cyclic aromatic hydrocarbons that do not contain
heteroatoms. Thus aryl groups include, but are not limited to,
phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl,
phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl,
biphenylenyl, anthracenyl, and naphthyl groups. In some
embodiments, aryl groups contain 6-14 carbons in the ring portions
of the groups. The phrase "aryl groups" includes groups containing
fused rings, such as fused aromatic-aliphatic ring systems (e.g.,
indanyl, tetrahydronaphthyl, and the like), and also includes
substituted aryl groups that have other groups, including but not
limited to alkyl, halo, amino, hydroxy, cyano, carboxy, nitro,
thio, or alkoxy groups, bonded to one of the ring atoms.
Representative substituted aryl groups can be mono-substituted or
substituted more than once, such as, but not limited to, 2-, 3-,
4-, 5-, or 6-substituted phenyl or naphthyl groups, which can be
substituted with groups including but not limited to those listed
above.
Aralkyl groups are alkyl, alkenyl or alkynyl groups as defined
above in which a hydrogen atom of an alkyl, alkenyl or alkynyl
group is replaced with an aryl group as defined above.
Representative aralkyl groups include benzyl (--CH.sub.2phenyl),
phenylethyl (--CH.sub.2CH.sub.2phenyl) and phenylethylene
(--CH.dbd.CHphenyl) groups and fused (cycloalkylaryl)alkyl groups
such as 4-ethyl-indanyl. The aryl moiety or the alkyl, alkenyl or
alkynyl moiety or both are optionally substituted with other
groups, including but not limited to alkyl, halo, amino, hydroxy,
cyano, carboxy, nitro, thio, or alkoxy groups.
Heterocyclyl or heterocyclic groups include aromatic and
non-aromatic ring moieties containing 3 or more ring members, of
which one or more is a heteroatom such as, but not limited to, N,
O, S, or P. In some embodiments, heterocyclyl groups include 3 to
20 ring members, whereas other such groups have 3 to 15 ring
members, including for example single ring systems containing 5, 6
or 7 ring members. At least one ring contains a heteroatom, but
every ring in a polycyclic system need not contain a heteroatom.
For example, a dioxolanyl ring and a benzdioxolanyl ring system
(methylenedioxyphenyl ring system) are both heterocyclyl groups
within the meaning herein. A heterocyclyl group designated as a
C.sub.2-heterocyclyl can be a 5-ring with two carbon atoms and
three heteroatoms, a 6-ring with two carbon atoms and four
heteroatoms, and so forth. Likewise a C.sub.4-heterocyclyl can be a
5-ring with one heteroatom, a 6-ring with two heteroatoms, and so
forth. The number of carbon atoms plus the number of heteroatoms
sums up to equal the total number of ring atoms.
The term "heterocyclyl" includes fused ring species including those
having fused aromatic and non-aromatic groups. The phrase also
includes polycyclic and/or bridging ring systems containing a
heteroatom such as, but not limited to, quinuclidyl and
7-azabicyclo[2.2.1]heptane, and also includes heterocyclyl groups
that have substituents, including but not limited to alkyl, halo,
amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups,
bonded to one of the ring members. A heterocyclyl group as defined
herein can be a heteroaryl group or a partially or completely
saturated cyclic group including at least one ring heteroatom.
Heterocyclyl groups include, but are not limited to, pyrazinyl,
pyrimidinyl, pyridazinyl, thiadiazolyl, oxadiazolyl, imidazolinyl,
hexahydropyrimidinyl, diazepanyl, triazinyl, imidazolyl,
pyrrolidinyl, furanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl,
dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl,
pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl,
pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl,
dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl,
indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl,
benzothiazolyl, benzothiadiazolyl, imidazopyridinyl,
isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,
guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,
quinoxalinyl, and quinazolinyl groups. Heterocyclyl groups can be
substituted. Representative substituted heterocyclyl groups can be
mono-substituted or substituted more than once, including but not
limited to, rings containing at least one heteroatom which are
mono, di, tri, tetra, penta, hexa, or higher-substituted with
substituents such as those listed above, including but not limited
to alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, and
alkoxy groups, and in the case of two substituents on the same
carbon atom of the heterocycle include oxo (.dbd.O) and thioxo
(.dbd.S).
Heteroaryl groups are aromatic ring moieties containing 5 or more
ring members, of which, one or more is a heteroatom such as, but
not limited to, N, O, and S. A heteroaryl group designated as a
C.sub.2-heteroaryl can be a 5-ring with two carbon atoms and three
heteroatoms, a 6-ring with two carbon atoms and four heteroatoms
and so forth. Likewise a C.sub.4-heteroaryl can be a 5-ring with
one heteroatom, a 6-ring with two heteroatoms, and so forth. The
number of carbon atoms plus the number of heteroatoms sums up to
equal the total number of ring atoms. Heteroaryl groups include,
but are not limited to, groups such as pyrrolyl, pyrazolyl,
pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, pyrazinyl, pyrimidinyl,
thiadiazolyl, imidazolyl, oxadiazolyl, thienyl, triazolyl,
tetrazolyl, triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl,
benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl,
benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl,
benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl,
thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl,
quinolinyl, isoquinolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups. The
terms "heteroaryl" and "heteroaryl groups" include fused ring
compounds such as wherein at least one ring, but not necessarily
all rings, are aromatic, including tetrahydroquinolinyl,
tetrahydroisoquinolinyl, indolyl and 2,3-dihydro indolyl. The term
also includes heteroaryl groups that have other groups bonded to
one of the ring members, including but not limited to alkyl, halo,
amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups.
Representative substituted heteroaryl groups can be substituted one
or more times with groups such as those listed above.
Additional examples of aryl and heteroaryl groups include but are
not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl,
2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl,
N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl,
3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl,
3-furyl), indolyl, oxadiazolyl (1,2,4-oxadiazolyl,
1,3,4-oxadiazolyl), thiadiazolyl (1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl), isoxazolyl, quinazolinyl, fluorenyl,
xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl
(2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl,
2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl
(1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl,
1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),
thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl
(2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl (2-pyrimidinyl,
4-pyrimidinyl, 5-pyrimidinyl, 6pyrimidinyl), pyrazinyl, pyridazinyl
(3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl),
prazolo[1,5-c]pyridinyl, quinolyl (2-quinolyl, 3-quinolyl,
4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl),
isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,
5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl),
benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl,
4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl,
7-benzo[b]furanyl), isobenzofuranyl, 2,3-dihydro-benzo[b]furanyl
(2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl),
4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl),
6-(2,3-dihydro-benzo[b]furanyl), 7-(2, 3-dihydro-benzo[b]furanyl),
benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl,
4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl,
7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl,
(2-(2,3-dihydro-benzo[b]thiophenyl),
3-(2,3-dihydro-benzo[b]thiophenyl),
4-(2,3-dihydro-benzo[b]thiophenyl),
5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,
3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl),
indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl,
6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl,
4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl
(1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl,
5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,
8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl),
benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl,
4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl,
7-benzothiazolyl), benzo[d]isoxazolyl, carbazolyl (1-carbazolyl,
2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine
(5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl,
5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl,
5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine
(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,
10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,
10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,
10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,
10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.
Heterocyclylalkyl groups are alkyl, alkenyl or alkynyl groups as
defined above in which a hydrogen or carbon bond of an alkyl,
alkenyl or alkynyl group is replaced with a bond to a heterocyclyl
group as defined above. Representative heterocyclyl alkyl groups
include, but are not limited to, furan-2-yl methyl, furan-3-yl
methyl, pyridine-2-yl methyl (.alpha.-picolyl), pyridine-3-yl
methyl (.beta.-picolyl), pyridine-4-yl methyl (.gamma.-picolyl),
tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
Heterocyclylalkyl groups can be substituted on the heterocyclyl
moiety, the alkyl, alkenyl or alkynyl moiety, or both.
Heteroarylalkyl groups are alkyl, alkenyl or alkynyl groups as
defined above in which a hydrogen or carbon bond of an alkyl,
alkenyl or alkynyl group is replaced with a bond to a heteroaryl
group as defined above. Heteroarylalkyl groups can be substituted
on the heteroaryl moiety, the alkyl, alkenyl or alkynyl moiety, or
both.
By a "ring system" as the term is used herein is meant a moiety
comprising one, two, three or more rings, which can be substituted
with non-ring groups or with other ring systems, or both, which can
be fully saturated, partially unsaturated, fully unsaturated, or
aromatic, and when the ring system includes more than a single
ring, the rings can be fused, bridging, or spirocyclic. By
"spirocyclic" is meant the class of structures wherein two rings
are fused at a single tetrahedral carbon atom, as is well known in
the art.
A "monocyclic, bicyclic or polycyclic, aromatic or partially
aromatic ring" as the term is used herein refers to a ring system
including an unsaturated ring possessing 4n+2 pi electrons, or a
partially reduced (hydrogenated) form thereof. The aromatic or
partially aromatic ring can include additional fused, bridged, or
spiro rings that are not themselves aromatic or partially aromatic.
For example, naphthalene and tetrahydronaphthalene are both a
"monocyclic, bicyclic or polycyclic, aromatic or partially aromatic
ring" within the meaning herein. Also, for example, a
benzo-[2.2.2]-bicyclooctane is also a "monocyclic, bicyclic or
polycyclic, aromatic or partially aromatic ring" within the meaning
herein, containing a phenyl ring fused to a bridged bicyclic
system. A fully saturated ring has no double bonds therein, and is
carbocyclic or heterocyclic depending on the presence of
heteroatoms within the meaning herein.
When two "R" groups are said to be joined together or taken
together to form a ring, it is meant that together with the carbon
atom or a non-carbon atom (e.g., nitrogen atom), to which they are
bonded, they may form a ring system. In general, they are bonded to
one another to form a 3- to 7-membered ring, or a 5- to 7-membered
ring. Non-limiting specific examples are the cyclopentyl,
cyclohexyl, cycloheptyl, piperidinyl, piperazinyl, pyrolidinyl,
pyrrolyl, pyridinyl.
The term "alkoxy" refers to an oxygen atom connected to an alkyl
group, including a cycloalkyl group, as are defined above. Examples
of linear alkoxy groups include but are not limited to methoxy,
ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy,
n-octyloxy n-nonyloxy, and the like. Examples of branched alkoxy
include but are not limited to isopropoxy, sec-butoxy, tert-butoxy,
isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy
include but are not limited to cyclopropyloxy, cyclobutyloxy,
cyclopentyloxy, cyclohexyloxy, and the like.
The terms "aryloxy" and "arylalkoxy" refer to, respectively, an
aryl group bonded to an oxygen atom and an aralkyl group bonded to
the oxygen atom at the alkyl moiety. Examples include but are not
limited to phenoxy, naphthyloxy, and benzyloxy.
An "acyl" group as the term is used herein refers to a group
containing a carbonyl moiety wherein the group is bonded via the
carbonyl carbon atom. The carbonyl carbon atom is also bonded to
another carbon atom, which can be part of an alkyl, aryl, aralkyl
cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, heteroarylalkyl group or the like. In the special case
wherein the carbonyl carbon atom is bonded to a hydrogen, the group
is a "formyl" group, an acyl group as the term is defined herein.
An acyl group can include 0 to about 12-20 additional carbon atoms
bonded to the carbonyl group. An acyl group can include double or
triple bonds within the meaning herein. An acryloyl group is an
example of an acyl group. An acyl group can also include
heteroatoms within the meaning here. A nicotinoyl group
(pyridyl-3-carbonyl) group is an example of an acyl group within
the meaning herein. Other examples include acetyl, benzoyl,
phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the
like. When the group containing the carbon atom that is bonded to
the carbonyl carbon atom contains a halogen, the group is termed a
"haloacyl" group. An example is a trifluoroacetyl group.
The term "amine" includes primary, secondary, and tertiary amines
having, e.g., the formula N(group).sub.3 wherein each group can
independently be H or non-H, such as alkyl, aryl, and the like.
Amines include but are not limited to R--NH.sub.2, for example,
alkylamines, arylamines, alkylarylamines; R.sub.2NH wherein each R
is independently selected, such as dialkylamines, diarylamines,
aralkylamines, heterocyclylamines and the like; and R.sub.3N
wherein each R is independently selected, such as trialkylamines,
dialkylarylamines, alkyldiarylamines, triarylamines, and the like.
The term "amine" also includes ammonium ions as used herein.
An "amino" group is a substituent of the form --NH.sub.2, --NHR,
--NR.sub.2, --NR.sub.3.sup.+, wherein each R is independently
selected, and protonated forms of each. Accordingly, any compound
substituted with an amino group can be viewed as an amine.
An "ammonium" ion includes the unsubstituted ammonium ion
NH.sub.4.sup.+, but unless otherwise specified, it also includes
any protonated or quaternarized forms of amines. Thus,
trimethylammonium hydrochloride and tetramethylammonium chloride
are both ammonium ions, and amines, within the meaning herein.
The term "amide" (or "amido") includes C-- and N-amide groups,
i.e., --C(O)NR.sub.2, and --NRC(O)R groups, respectively. Amide
groups therefore include but are not limited to carbamoyl groups
(--C(O)NH.sub.2) and formamide groups (--NHC(O)H). A "carboxamido"
group is a group of the formula C(O)NR.sub.2, wherein R can be H,
alkyl, aryl, etc.
The term "carbonyl," refers to a --C(O)-- group.
"Halo," "halogen," and "halide" include fluorine, chlorine, bromine
and iodine.
The term "perhaloalkyl" refers to an alkyl group where all of the
hydrogen atoms are replaced by halogen atoms. Perhaloalkyl groups
include, but are not limited to, --CF.sub.3 and
--C(CF.sub.3).sub.3. The term "haloalkyl" refers to an alkyl group
where some but not necessarily all of the hydrogen atoms are
replaced by halogen atoms. Haloalkyl groups include but are not
limited to --CHF.sub.2 and --CH.sub.2F.
The term "perhaloalkoxy" refers to an alkoxy group where all of the
hydrogen atoms are replaced by halogen atoms. Perhaloalkoxy groups
include, but are not limited to, --OCF.sub.3 and
--OC(CF.sub.3).sub.3. The term "haloalkoxy" refers to an alkoxy
group where some but not necessarily all of the hydrogen atoms are
replaced by halogen atoms. Haloalkoxy groups include but are not
limited to --OCHF.sub.2 and --OCH.sub.2F.
The terms "comprising," "including," "having," "composed of," are
open-ended terms as used herein, and do not preclude the existence
of additional elements or components. In a claim element, use of
the forms "comprising," "including," "having," or "composed of"
means that whatever element is comprised, had, included, or
composes is not necessarily the only element encompassed by the
subject of the clause that contains that word.
A "salt" as is well known in the art includes an organic compound
such as a carboxylic acid, a sulfonic acid, or an amine, in ionic
form, in combination with a counterion. For example, acids in their
anionic form can form salts with cations such as metal cations, for
example sodium, potassium, and the like; with ammonium salts such
as NH.sub.4.sup.+ or the cations of various amines, including
tetraalkyl ammonium salts such as tetramethylammonium, or other
cations such as trimethylsulfonium, and the like. A
"pharmaceutically acceptable" or "pharmacologically acceptable"
salt is a salt formed from an ion that has been approved for human
consumption and is generally non-toxic, such as a chloride salt or
a sodium salt. A "zwitterion" is an internal salt such as can be
formed in a molecule that has at least two ionizable groups, one
forming an anion and the other a cation, which serve to balance
each other. For example, amino acids such as glycine can exist in a
zwitterionic form. A "zwitterion" is a salt within the meaning
herein. The compounds of the present invention may take the form of
salts. The term "salts" embraces addition salts of free acids or
free bases which are compounds of the invention. Salts can be
"pharmaceutically-acceptable salts." The term
"pharmaceutically-acceptable salt" refers to salts which possess
toxicity profiles within a range that affords utility in
pharmaceutical applications. Pharmaceutically unacceptable salts
may nonetheless possess properties such as high crystallinity,
which have utility in the practice of the present invention, such
as for example utility in process of synthesis, purification or
formulation of compounds of the invention.
Suitable pharmaceutically-acceptable acid addition salts may be
prepared from an inorganic acid or from an organic acid. Examples
of inorganic acids include hydrochloric, hydrobromic, hydriodic,
nitric, carbonic, sulfuric, and phosphoric acids. Appropriate
organic acids may be selected from aliphatic, cycloaliphatic,
aromatic, araliphatic, heterocyclic, carboxylic and sulfonic
classes of organic acids, examples of which include formic acetic,
propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,
citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic,
glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic,
mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,
benzenesulfonic, panthothenic, trifluoromethanesulfonic,
2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic,
cyclohexylaminosulfonic, stearic, alginic, .beta.-hydroxybutyric,
salicylic, galactaric and galacturonic acid. Examples of
pharmaceutically unacceptable acid addition salts include, for
example, perchlorates and tetrafluoroborates.
Suitable pharmaceutically acceptable base addition salts of
compounds of the invention include, for example, metallic salts
including alkali metal, alkaline earth metal and transition metal
salts such as, for example, calcium, magnesium, potassium, sodium
and zinc salts. Pharmaceutically acceptable base addition salts
also include organic salts made from basic amines such as, for
example, N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine. Examples of pharmaceutically unacceptable base addition
salts include lithium salts and cyanate salts. Although
pharmaceutically unacceptable salts are not generally useful as
medicaments, such salts may be useful, for example as intermediates
in the synthesis of Formula I compounds, for example in their
purification by recrystallization. All of these salts may be
prepared by conventional means from the corresponding compound
according to Formula I by reacting, for example, the appropriate
acid or base with the compound according to Formula I. The term
"pharmaceutically acceptable salts" refers to nontoxic inorganic or
organic acid and/or base addition salts, see, for example, Lit et
al., Salt Selection for Basic Drugs (1986), Int J. Pharm., 33,
201-217, incorporated by reference herein.
A "hydrate" is a compound that exists in a composition with water
molecules. The composition can include water in stoichiometric
quantities, such as a monohydrate or a dihydrate, or can include
water in random amounts. As the term is used herein a "hydrate"
refers to a solid form, i.e., a compound in water solution, while
it may be hydrated, is not a hydrate as the term is used
herein.
A "solvate" is a similar composition except that a solvent other
that water replaces the water. For example, methanol or ethanol can
form an "alcoholate", which can again be stoichiometric or
non-stoichiometric. As the term is used herein a "solvate" refers
to a solid form, i.e., a compound in solution in a solvent, while
it may be solvated, is not a solvate as the term is used
herein.
A "prodrug" as is well known in the art is a substance that can be
administered to a patient where the substance is converted in vivo
by the action of biochemicals within the patient's body, such as
enzymes, to the active pharmaceutical ingredient. Examples of
prodrugs include esters of carboxylic acid groups, which can be
hydrolyzed by endogenous esterases as are found in the bloodstream
of humans and other mammals.
"Isotopes" are well known in the art and refer to atoms with the
same number of protons but different number of neutrons. For
example, carbon 12, the most common form of carbon, has six protons
and six neutrons, whereas carbon 14 has six protons and eight
neutrons.
In addition, where features or aspects of the invention are
described in terms of Markush groups, those skilled in the art will
recognize that the invention is also thereby described in terms of
any individual member or subgroup of members of the Markush group.
For example, if X is described as selected from the group
consisting of bromine, chlorine, and iodine, claims for X being
bromine and claims for X being bromine and chlorine are fully
described. Moreover, where features or aspects of the invention are
described in terms of Markush groups, those skilled in the art will
recognize that the invention is also thereby described in terms of
any combination of individual members or subgroups of members of
Markush groups. Thus, for example, if X is described as selected
from the group consisting of bromine, chlorine, and iodine, and Y
is described as selected from the group consisting of methyl,
ethyl, and propyl, claims for X being bromine and Y being methyl
are fully described.
The GLP-1 compounds, their pharmaceutically acceptable salts or
hydrolyzable esters of the present invention may be combined with a
pharmaceutically acceptable carrier to provide pharmaceutical
compositions useful for treating the biological conditions or
disorders noted herein in mammalian species, and more preferably,
in humans. The particular carrier employed in these pharmaceutical
compositions may vary depending upon the type of administration
desired (e.g., intravenous, oral, topical, suppository, or
parenteral).
In preparing the compositions in oral liquid dosage forms (e.g.,
suspensions, elixirs and solutions), typical pharmaceutical media,
such as water, glycols, oils, alcohols, flavoring agents,
preservatives, coloring agents and the like can be employed.
Similarly, when preparing oral solid dosage forms (e.g., powders,
tablets and capsules), carriers such as starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and
the like can be employed.
Another aspect of an embodiment of the invention provides
compositions of the compounds of the invention, alone or in
combination with another GLP-1 agonist or another type of
therapeutic agent or second medicament, or both. Non-limiting
examples of the GLP-1 receptor agonists include exenatide,
liraglutide, taspoglutide, albiglutide, lixisenatide, and mixtures
thereof.
In one embodiment, the GLP-1 agonist is exenatide (Byetta.RTM.) or
Byetta LAR.RTM.. Exenatide is described, for example, in U.S. Pat.
Nos. 5,424,286; 6,902,744; 7,297,761, and others, the contents of
each of which is herein incorporated by reference in its
entirety.
In one embodiment, the GLP-1 agonist is liraglutide (VICTOZA.RTM.)
(also called NN-2211 and [Arg34,
Lys26]-(N-epsilon-(gamma-Glu(N-alpha-hexadecanoyl))-GLP-1 (7-37)),
includes the sequence HAEGTFTSDVSSYLEGQAAKEFIAWKVRGRG (SEQ ID NO:
1) and is available from Novo Nordisk (Denmark) or Scios (Fremont,
Calif. USA). See, e.g., Elbrond et al., 2002, Diabetes Care.
August; 25(8):1398404; Agerso et al., 2002, Diabetologia. February;
45(2):195-202).
In one embodiment, the GLP-1 agonist is taspoglutide (CAS Registry
No. 275371-94-3) and is available from Hoffman La-Roche. See, for
example, U.S. Pat. No. 7,368,427, the contents of which are herein
incorporated by reference in its entirety.
In one embodiment, the GLP-1 agonist albiglutide (SYNCRIA.RTM. from
GlaxoSmithKline).
In another embodiment, the GLP-1 agonist is lixisenatide
(Lyxumia.RTM. from Sanofi-Aventis/Zealand Pharma).
Non-limiting examples of the second medicaments are as disclosed
above. In various such embodiments, the second medicament is
exenatide, liraglutide, taspoglutide, albiglutide, or lixisenatide
or other insulin regulating peptide. In various such embodiments,
the second medicament is a DPPIV inhibitor. In various such
embodiments, the second medicament is medically indicated for the
treatment of type II diabetes. In various such embodiments, the
second medicament is a biguanide, a sulfonylurea, a meglitinide, a
thiazolidinedione, an .alpha.-glucosidase inhibitor, a bile acid
sequestrant, an SGLT-2 inhibitor, and/or a dopamine-2 agonist.
In another embodiment, the second medicament is metformin.
In another embodiment, the second medicament is sitagliptin.
As set forth herein, compounds of the invention include
stereoisomers, tautomers, solvates, hydrates, salts including
pharmaceutically acceptable salts, and mixtures thereof.
Compositions containing a compound of the invention can be prepared
by conventional techniques, e.g., as described in Remington: The
Science and Practice of Pharmacy, 19th Ed., 1995, incorporated by
reference herein. The compositions can appear in conventional
forms, for example capsules, tablets, aerosols, solutions,
suspensions or topical applications.
Typical compositions include a compound of the invention and a
pharmaceutically acceptable excipient which can be a carrier or a
diluent. For example, the active compound will usually be mixed
with a carrier, or diluted by a carrier, or enclosed within a
carrier which can be in the form of an ampoule, capsule, sachet,
paper, or other container. When the active compound is mixed with a
carrier, or when the carrier serves as a diluent, it can be solid,
semi-solid, or liquid material that acts as a vehicle, excipient,
or medium for the active compound. The active compound can be
adsorbed on a granular solid carrier, for example contained in a
sachet. Some examples of suitable carriers are water, salt
solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated
castor oil, peanut oil, olive oil, gelatin, lactose, terra alba,
sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin,
amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia,
stearic acid or lower alkyl ethers of cellulose, silicic acid,
fatty acids, fatty acid amines, fatty acid monoglycerides and
diglycerides, pentaerythritol fatty acid esters, polyoxyethylene,
hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the
carrier or diluent can include any sustained release material known
in the art, such as glyceryl monostearate or glyceryl distearate,
alone or mixed with a wax.
The formulations can be mixed with auxiliary agents which do not
deleteriously react with the active compounds. Such additives can
include wetting agents, emulsifying and suspending agents, salt for
influencing osmotic pressure, buffers and/or coloring substances
preserving agents, sweetening agents or flavoring agents. The
compositions can also be sterilized if desired.
The route of administration can be any route which effectively
transports the active compound of the invention to the appropriate
or desired site of action, such as oral, nasal, pulmonary, buccal,
subdermal, intradermal, transdermal or parenteral, e.g., rectal,
depot, subcutaneous, intravenous, intraurethral, intramuscular,
intranasal, ophthalmic solution or an ointment, the oral route
being preferred.
For parenteral administration, the carrier will typically comprise
sterile water, although other ingredients that aid solubility or
serve as preservatives can also be included. Furthermore,
injectable suspensions can also be prepared, in which case
appropriate liquid carriers, suspending agents and the like can be
employed.
For topical administration, the compounds of the present invention
can be formulated using bland, moisturizing bases such as ointments
or creams.
If a solid carrier is used for oral administration, the preparation
can be tabletted, placed in a hard gelatin capsule in powder or
pellet form or it can be in the form of a troche or lozenge. If a
liquid carrier is used, the preparation can be in the form of a
syrup, emulsion, soft gelatin capsule or sterile injectable liquid
such as an aqueous or non-aqueous liquid suspension or
solution.
Injectable dosage forms generally include aqueous suspensions or
oil suspensions which can be prepared using a suitable dispersant
or wetting agent and a suspending agent Injectable forms can be in
solution phase or in the form of a suspension, which is prepared
with a solvent or diluent. Acceptable solvents or vehicles include
sterilized water, Ringer's solution, or an isotonic aqueous saline
solution. Alternatively, sterile oils can be employed as solvents
or suspending agents. Preferably, the oil or fatty acid is
non-volatile, including natural or synthetic oils, fatty acids,
mono-, di- or tri-glycerides.
For injection, the formulation can also be a powder suitable for
reconstitution with an appropriate solution as described above.
Examples of these include, but are not limited to, freeze dried,
rotary dried or spray dried powders, amorphous powders, granules,
precipitates, or particulates. For injection, the formulations can
optionally contain stabilizers, pH modifiers, surfactants,
bioavailability modifiers and combinations of these. The compounds
can be formulated for parenteral administration by injection such
as by bolus injection or continuous infusion. A unit dosage form
for injection can be in ampoules or in multi-dose containers.
The formulations of the invention can be designed to provide quick,
sustained, or delayed release of the active ingredient after
administration to the patient by employing procedures well known in
the art. Thus, the formulations can also be formulated for
controlled release or for slow release.
Compositions contemplated by the present invention can include, for
example, micelles or liposomes, or some other encapsulated form, or
can be administered in an extended release form to provide a
prolonged storage and/or delivery effect. Therefore, the
formulations can be compressed into pellets or cylinders and
implanted intramuscularly or subcutaneously as depot injections.
Such implants can employ known inert materials such as silicones
and biodegradable polymers, e.g., polylactide-polyglycolide.
Examples of other biodegradable polymers include poly(orthoesters)
and poly(anhydrides).
For nasal administration, the preparation can contain a compound of
the invention, dissolved or suspended in a liquid carrier,
preferably an aqueous carrier, for aerosol application. The carrier
can contain additives such as solubilizing agents, e.g., propylene
glycol, surfactants, absorption enhancers such as lecithin
(phosphatidylcholine) or cyclodextrin, or preservatives such as
parabens.
For parenteral application, particularly suitable are injectable
solutions or suspensions, preferably aqueous solutions with the
active compound dissolved in polyhydroxylated castor oil.
Dosage forms can be administered daily, or more than once a day,
such as twice or thrice daily. Alternatively dosage forms can be
administered less frequently than daily, such as every other day,
or weekly, if found to be advisable by a prescribing physician.
Dosing regimens include, for example, dose titration to the extent
necessary or useful for the indication to be treated, thus allowing
the patient's body to adapt to the treatment and/or to minimize or
avoid unwanted side effects associated with the treatment. Other
dosage forms include delayed or controlled-release forms. Suitable
dosage regimens and/or forms include those set out, for example, in
the latest edition of the Physicians' Desk Reference, incorporated
herein by reference.
An embodiment of the invention also encompasses prodrugs of a
compound of the invention which on administration undergo chemical
conversion by metabolic or other physiological processes before
becoming active pharmacological substances. Conversion by metabolic
or other physiological processes includes without limitation
enzymatic (e.g., specific enzymatically catalyzed) and
non-enzymatic (e.g., general or specific acid or base induced)
chemical transformation of the prodrug into the active
pharmacological substance. In general, such prodrugs will be
functional derivatives of a compound of the invention which are
readily convertible in vivo into a compound of the invention.
Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described, for example, in Design
of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
In another embodiment, there are provided methods of making a
composition of a compound described herein including formulating a
compound of the invention with a pharmaceutically acceptable
carrier or diluent. In some embodiments, the pharmaceutically
acceptable carrier or diluent is suitable for oral administration.
In some such embodiments, the methods can further include the step
of formulating the composition into a tablet or capsule. In other
embodiments, the pharmaceutically acceptable carrier or diluent is
suitable for parenteral administration. In some such embodiments,
the methods further include the step of lyophilizing the
composition to form a lyophilized preparation.
The compounds of the invention can be used therapeutically in
combination with i) one or more other GLP-1 modulators and/or ii)
one or more other types of therapeutic agents or second medicaments
which can be administered orally in the same dosage form, in a
separate oral dosage form (e.g., sequentially or non-sequentially)
or by injection together or separately (e.g., sequentially or
non-sequentially). Examples of combination therapeutic agents
include Metformin, Sitagliptin (MK-0431, Januvia) an oral
antihyperglycemic (antidiabetic drug) of the dipeptidyl peptidase-4
(DPP-4) inhibitor class and Exenatide (Byetta) an incretin mimetic.
In other embodiments, the second medicament is a biguanide such as
metformin, a sulfonylurea such as glibenclamide, glipizide,
gliclazide, and glimepiride, a meglitinide such as repaglinide and
nateglinide, a thiazolidinedione such as pioglitazone and
rosiglitazone, an .alpha.-glucosidase inhibitor such as acarbose
and miglitol, a bile acid sequestrant such as colesevelam, and/or a
dopamine-2 agonist such as bromocriptine.
Combinations of the invention include mixtures of compounds from i)
and ii) in a single formulation and compounds from i) and ii) as
separate formulations. Some combinations of the invention can be
packaged as separate formulations in a kit. In some embodiments,
two or more compounds from ii) are formulated together while a
compound of the invention is formulated separately.
The dosages and formulations for the other agents to be employed,
where applicable, will be as set out in the latest edition of the
Physicians' Desk Reference, incorporated herein by reference.
In certain embodiments, the present invention encompasses compounds
that bind with high affinity and specificity to the GLP-1 receptor
in an agonist manner or as an activator or a potentiator. In
certain embodiments a compound of the invention acts as a positive
allosteric modulator of GLP-1 receptor.
In certain embodiments, the present invention provides a method for
activating, potentiating, or agonizing (i.e., to have an agonic
effect, to act as an agonist) a GLP-1 receptor, with a compound of
the invention. The method involves contacting the receptor with a
suitable concentration of an inventive compound to bring about
activation of the receptor. The contacting can take place in vitro,
for example in carrying out an assay to determine the GLP-1
receptor activation activity of an inventive compound undergoing
experimentation related to a submission for regulatory
approval.
In certain embodiments, the method for activating a GLP-1 receptor,
can also be carried out in vivo, that is, within the living body of
a mammal, such as a human patient or a test animal. The inventive
compound can be supplied to the living organism via one of the
routes as described above, e.g., orally, or can be provided locally
within the body tissues. In the presence of the inventive compound,
activation of the receptor takes place, and the effect thereof can
be studied.
An embodiment of the present invention provides a method of
treatment of a malcondition in a patient for which activation of an
GLP-1 receptor is medically indicated, wherein the patient is
administered the inventive compound in a dosage, at a frequency,
and for a duration to produce a beneficial effect on the patient.
The inventive compound can be administered by any suitable means,
examples of which are described above.
In certain embodiments, the present invention is directed to
compounds adapted to act as modulators or potentiators of Class B
GPCRs. These compounds may have activity on their own or in the
presence of receptor ligands. Receptors include incretin peptides
including GLP-1(7-36) and GLP-1(9-36).
Methods of treatments provided by the invention include
administration of a compound of the invention, alone or in
combination with another pharmacologically active agent or second
medicament to a subject or patient having a malcondition for which
activation, potentiation or agonism of a glucagon-like peptide 1
receptor is medically indicated such as type I diabetes, type II
diabetes, gestational diabetes, obesity, excessive appetite,
insufficient satiety, or metabolic disorder.
In another embodiment, methods of treatment provided by the
invention include administration of a compound of the invention for
the treatment of non-alcoholic fatty liver disease (NAFLD) and/or
non-alcoholic steatohepatitis (NASH). NAFLD is believed to be
caused by the disruption of hepatic lipid homeostasis and, at least
in a portion of patients, can progress to NASH. NAFLD is associated
with insulin resistance in type 2 diabetes mellitus, and GLP1
increases insulin sensitivity and aids glucose metabolism. The
compounds of this invention are beneficial in this context by
serving to increase fatty acid oxidation, decrease lipogenesis,
and/or improve hepatic glucose metabolism (see e.g., Lee et. al.,
Diabetes Metab. J. 36:262-267, 2012; Trevaskis et al. Am. J.
Physiol. Gastrointest. Liver Physiol. 302:G762-G772, 2012; Kim et
al. Korean J. Physiol. Pharmacol. 18:333-339, 2014; and see:
Armstrong et. al., Journal of Hepatology 62:S187-S212, 2015 for
results with Liraglutide in Phase II trials).
General Synthetic Methods for Preparing Compounds
Molecular embodiments of the present invention can be synthesized
using standard synthetic techniques known to those of skill in the
art. Compounds of the present invention can be synthesized using
the general synthetic procedures set forth in Schemes 1-53.
##STR00077##
The other enantiomer can be prepared in a similar manner using
Scheme 1.
##STR00078##
##STR00079##
The other enantiomer can be prepared in a similar manner using
Scheme 3.
##STR00080##
The other enantiomer can be prepared in a similar manner using
Scheme 4.
##STR00081##
The other enantiomer can be prepared in a similar manner using
Scheme 5.
##STR00082##
The other enantiomer can be prepared in a similar manner using
Scheme 6.
##STR00083##
The other enantiomer can be prepared in a similar manner using
Scheme 7.
##STR00084##
The other enantiomer can be prepared in a similar manner using
Scheme 8.
##STR00085##
The other enantiomer can be prepared in a similar manner using
Scheme 9.
##STR00086##
The other enantiomer can be prepared in a similar manner using
Scheme 10.
##STR00087##
The other enantiomer can be prepared in a similar manner using
Scheme 11.
##STR00088##
The other enantiomer can be prepared in a similar manner using
Scheme 12.
##STR00089##
The other enantiomer can be prepared in a similar manner using
Scheme 13.
##STR00090##
The other enantiomer can be prepared in a similar manner using
Scheme 14.
##STR00091##
##STR00092##
##STR00093##
The other enantiomer can be prepared in a similar manner using
Scheme 17.
##STR00094##
The other enantiomer can be prepared in a similar manner using
Scheme 18.
##STR00095##
The other enantiomer can be prepared in a similar manner using
Scheme 19.
##STR00096##
The other enantiomer and diastereoisomer can be prepared in a
similar manner using Scheme 20.
##STR00097##
The other enantiomer can be prepared in a similar manner using
Scheme 21.
##STR00098##
The other enantiomer can be prepared in a similar manner using
Scheme 22.
##STR00099##
The other enantiomer can be prepared in a similar manner using
Scheme 23.
##STR00100##
The other enantiomer can be prepared in a similar manner using
Scheme 24.
##STR00101##
The other enantiomer can be prepared in a similar manner using
Scheme 25.
##STR00102##
The other enantiomer can be prepared in a similar manner using
Scheme 26.
##STR00103##
The other enantiomer and diastereomers can be prepared in a similar
manner using Scheme 27.
##STR00104##
The other enantiomer can be prepared in a similar manner using
Scheme 28.
##STR00105##
The other enantiomer can be prepared in a similar manner using
Scheme 29.
##STR00106##
The other enantiomer can be prepared in a similar manner using
Scheme 30.
##STR00107##
The other enantiomer can be prepared in a similar manner using
Scheme 31.
##STR00108##
The other enantiomer can be prepared in a similar manner using
Scheme 32.
##STR00109##
The other enantiomer can be prepared in a similar manner using
Scheme 33.
##STR00110##
The other enantiomer can be prepared in a similar manner using
Scheme 34.
##STR00111##
The other enantiomer and diastereomers can be prepared in a similar
manner using Scheme 35.
##STR00112##
The other enantiomer and diastereoisomers can be prepared in a
similar manner using Scheme 36.
##STR00113##
The other enantiomer and diastereoisomers can be prepared in a
similar manner using Scheme 37.
##STR00114##
The other enantiomer can be prepared in a similar manner using
Scheme 38.
##STR00115##
The other enantiomer and diastereoisomers can be prepared in a
similar manner using Scheme 39.
##STR00116##
The other enantiomer can be prepared in a similar manner using
Scheme 40.
##STR00117##
The other enantiomer can be prepared in a similar manner using
Scheme 41.
##STR00118##
The other enantiomer can be prepared in a similar manner using
Scheme 42.
##STR00119##
The other enantiomer can be prepared in a similar manner using
Scheme 43.
##STR00120##
The other enantiomer can be prepared in a similar manner using
Scheme 43.
##STR00121##
The other enantiomer can be prepared in a similar manner using
Scheme 45.
##STR00122##
The other enantiomer and diastereoisomer can be prepared in a
similar manner using Scheme 46.
##STR00123##
The other enantiomer can be prepared in a similar manner using
Scheme 47.
##STR00124##
The other enantiomer can be prepared in a similar manner using
Scheme 48.
##STR00125##
##STR00126##
The other enantiomer can be prepared in a similar manner using
Scheme 50.
##STR00127##
The other enantiomer can be prepared in a similar manner using
Scheme 51.
##STR00128##
The other enantiomer can be prepared in a similar manner using
Scheme 52.
##STR00129##
The other enantiomer can be prepared in a similar manner using
Scheme 53.
EXAMPLES
The invention is further illustrated by the following examples. The
examples below are non-limiting are merely representative of
various aspects of the invention.
General Methods
NMR Spectra
.sup.1H NMR (400 MHz) and .sup.13C NMR (100 MHz) were obtained in
solution of deuteriochloroform (CDCl.sub.3) or dimethyl sulfoxide
(d.sub.6-DMSO). NMR spectra were processed using MestReNova
6.0.3-5604.
LCMS Data
Mass spectra (LCMS) were obtained using one of 6 systems. System
1a: Agilent 1100/6110 HPLC system equipped with a Thompson ODS-A,
100 A, 5.mu. (50.times.4.6 mm) column using water with 0.1% formic
acid as the mobile phase A, acetonitrile with 0.1% formic acid as
the mobile phase B, water with 5 mM ammonium acetate as the mobile
phase C, and acetonitrile with 5 mM ammonium acetate as the mobile
phase D with a flow rate of 1 mL/min. Method 1: 20-100% mobile
phase B (80-0% A) over 2.5 min then held at 100% B for 2.5 min.
Method 2: 5% mobile phase B (95% A) for 1 min, 5-95% B over 9 min,
then held at 95% B for 5 min. Method 3: 20-100% mobile phase B
(80-0% A) over 2.5 min then held at 100% B for 4.5 min. Method 12:
5% D (95% C) for 1 min. then 5-95% D over 9 min. and held at 95% D
for 5 min. System 1b: Agilent 1100/6110 HPLC system equipped with a
Agilent Poroshell 120 EC-C8, 2.7.mu. (50.times.3 mm) column using
water with 5 mM ammonium acetate as the mobile phase C, and
acetonitrile with 5 mM ammonium acetate as the mobile phase D with
a flow rate of 1 mL/min. Method 13: 5% D (95% C) to 95% D over 12
min. then held at 95% D for 2.8 min. and to 5% D over 0.2 min.
System 1c: Agilent 1100/6110 HPLC system equipped with a Agilent
Poroshell 120 EC-C18, 2.7.mu. (50.times.3 mm) column using water
with 5 mM ammonium acetate as the mobile phase C, and acetonitrile
with 5 mM ammonium acetate as the mobile phase D with a flow rate
of 1 mL/min. Method 14: 5% D (95% C) to 95% D over 12 min. then
held at 95% D for 2.8 min. and then to 5% D over 0.2 min. Method
15: 20% D (80% C) to 95% D over 3 min. and hold at 95% D 1.8 min
then to 20% D over 0.2 min. Method 16: 20% D (80% C) to 95% D over
3.0 min. and hold at 95% D for 3.8 min. then 20% D over 0.2 min.
System 1d: Agilent 1100/6110 HPLC system equipped with a Agilent
Poroshell 120 EC-C8, 2.7.mu. (50.times.3 mm) column using water
with 5 mM ammonium acetate as the mobile phase C, and acetonitrile
with 5 mM ammonium acetate as the mobile phase D with a flow rate
of 1 mL/min. Method 18: 20% D (80% C) to 95% D over 3 min. and hold
at 95% D 1.8 min then to 20% D over 0.2 min. Method 19: 20% D (80%
C) to 95% D over 3.0 min. and hold at 95% D for 3.8 min. then 20% D
over 0.2 min. Method 20: 5% D (95% C) to 95% D over 12 min then
held at 95% D for 2.8 min. and then to 5% D over 0.2 min. System
1e: Agilent 1100/6110 HPLC system equipped with a Waters X-Bridge
C-8, 3.5.mu. (50.times.4.6 mm) column using water with 5 mM
ammonium acetate as the mobile phase C, and acetonitrile with 5 mM
ammonium acetate as the mobile phase D with a flow rate of 1
mL/min. Method 25: 20% D (80% C) to 95% D over 3 min. then held at
95% D for 3.8 min. and then to 5% D over 0.2 min. Method 26: 20% D
(80% C) to 95% D over 3 min. and hold at 95% D 1.8 min then to 20%
D over 0.2 min. Method 28: 20% D (80% C) to 95% D over 12.0 min.
and hold at 95% D for 2.8 min. then 20% D over 0.2 min. System 2:
Agilent 1200 LCMS equipped with an Agilent Zorbax Extend RRHT 1.8
.mu.m (4.6.times.30 mm) column using water with 0.1% formic acid as
mobile phase A and acetonitrile with 0.1% formic acid as mobile
phase B. Method 4: 5-95% mobile phase B over 3.0 min with a flow
rate of 2.5 mL/min, then held at 95% for 0.5 min with a flow rate
of 4.5 mL/min. Method 5: 5-95% mobile phase B over 14 min with a
flow rate of 2.5 mL/min, then held at 95% for 0.5 min with a flow
rate of 4.5 mL/min. System 3: Waters Fractionlynx LCMS system
equipped with an Agilent Zorbax Extend RRHT 1.8 (4.6.times.30 mm)
column using water with 0.1% formic acid as mobile phase A and
acetonitrile with 0.1% formic acid as mobile phase B. Method 6:
5-95% mobile phase B over 3.0 min with a flow rate of 2.5 mL/min,
then held at 95% for 0.5 min with a flow rate of 4.5 mL/min. Method
7: 5-95% mobile phase B over 14 min with a flow rate of 2.5 mL/min,
then held at 95% for 0.5 min with a flow rate of 4.5 mL/min. System
4: Agilent 1260 LCMS equipped with an Agilent Zorbax Extend RRHT
1.8 .mu.m (4.6.times.30 mm) column using water with 0.1% formic
acid as mobile phase A and acetonitrile with 0.1% formic acid as
mobile phase B. Method 8: 5-95% mobile phase B over 3.0 min with a
flow rate of 2.5 mL/min, then held at 95% for 0.5 min with a flow
rate of 4.5 mL/min. Method 9: 5-95% mobile phase B over 14 min with
a flow rate of 2.5 mL/min, then held at 95% for 0.5 min with a flow
rate of 4.5 mL/min. System 5: Agilent 1260 LCMS equipped with a
Waters Xselect CSH C18 3.5 .mu.m (4.6.times.50 mm) column using
water with 0.1% formic acid as mobile phase A and acetonitrile with
0.1% formic acid as mobile phase B. Method 10: The gradient was
5-95% mobile phase B over 13.0 min with a flow rate of 2.5 mL/min,
then held at 95% for 1.0 min with a flow rate of 4.5 mL/min. Method
11: The gradient was 5-95% mobile phase B over 3.0 min with a flow
rate of 2.5 mL/min, then held at 95% for 0.6 min with a flow rate
of 4.5 mL/min. System 6: Waters Acquity UPLC system equipped with a
Acquity UPLC BEH C18, 1.7 .mu.m (2.1.times.50 mm) or Phenomenex
Kinetex C18, 1.7 .mu.m (2.1.times.50 mm) column using water with 10
mM ammonium formate as mobile phase A, acetonitrile as mobile phase
B with a flow rate of 0.5 mL/min. Method 17: 10% mobile phase B
(90% A) for 0.5 min, 10-95% B over 3 min, then held at 95% B for
1.1 min, 95-10% B over 0.1 min then held for 0.3 min and the total
run time is 5 min. Method 23: 20% mobile phase B (80% A) for 0.5
min, 20-95% B over 3 min, then held at 95% B for 1.1 min, 95-20% B
over 0.1 min, then held for 0.3 min and the total run time is 5
min. Method 24: 30% mobile phase B (70% A) for 0.5 min, 30-95% B
over 2.2 min, then held at 95% B for 1.9 min, 95-30% B over 0.1
min, then held for 0.3 min and the total run time is 5 min. Method
27: 40% mobile phase B (60% A) for 0.5 min, 40-95% B over 1.9 min,
then held at 95% B for 2.2 min, 95-40% B over 0.1 min, then held
for 0.3 min and the total run time is 5 min. Method 21: 20% mobile
phase B (80% A) for 0.5 min, 20-95% B over 2.7 min, then held at
95% B for 1.4 min, 95-20% B over 0.1 min, then held for 0.3 min and
the total run time is 5 min. Method 22: 40% mobile phase B (60% A)
for 0.5 min, 40-95% B over 1.6 min, then held at 95% B for 2.5 min,
95-40% B over 0.1 min, then held for 0.3 min and the total run time
is 5 min.
Hydrogenations
Hydrogenation reactions were performed using a Thales
Nanotechnology H-Cube reactor equipped with the specified CatCart
or using standard laboratory techniques.
Reaction Conditions and Abbreviations
Pyridine, dichloromethane (DCM), tetrahydrofuran (THF), and toluene
used in the procedures were from Aldrich Sure-Seal bottles or Acros
AcroSeal dry solvent and kept under nitrogen (N.sub.2). All
reactions were stirred magnetically and temperatures are external
reaction temperatures. The following abbreviations are used: ethyl
acetate (EA), 1-methy-2-pyrrolidinone (NMP), triethylamine (TEA),
N-hydroxybenzotriazole (HOBt), 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide hydrochloride (EDC), N,N-dimethylformamide (DMF),
dimethyl acetamide (DMA), Di-tert-butyl dicarbonate (Boc.sub.2O),
N,N-Diisopropylethylamine (DIEA), acetic acid (AcOH), hydrochloric
acid (HCl), O-(7-azabenzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP),
tert-butanol (t-BuOH), sodium hydride (NaH), sodium
triacetoxyborohydride (Na(OAc).sub.3BH), ethanol (EtOH), methanol
(MeOH), acetonitrile (ACN).
Purifications
Chromatographies were carried out using a Combiflash Rf flash
purification system (Teledyne Isco) equipped with Redisep (Teledyne
Isco), Telos (Kinesis) or Grace Resolv (Grace Davison Discovery
Sciences) silica gel (SiO.sub.2) columns. Preparative HPLC
purifications were performed using one or two systems. System 1:
Varian ProStar/PrepStar system equipped with a Waters SunFire Prep
C18 OBD, 5 .mu.m (19.times.150 mm) column using water containing
0.05% trifluoroacetic acid as mobile phase A, and acetonitrile with
0.05% trifluoroacetic acid as mobile phase B. The gradient was
40-95% mobile phase B over 10 min, held at 95% for 5-10 min, and
then return to 40% over 2 min with flow rate of 18 mL/min.
Fractions were collected using a Varian Prostar fraction collector
by UV detection at 254 nm and were evaporated using a Savant
SpeedVac Plus vacuum pump or a Genevac EZ-2.System 2: Waters
Fractionlynx system equipped with an Agilent Prep-C18, 5 .mu.m
(21.2.times.50 mm) column using water containing 0.1% formic acid
as mobile phase A, and acetonitrile with 0.1% formic acid as mobile
phase B. The gradient was 45-95% mobile phase B over 7.5 min, held
at 95% for 1 min, and then returned to 45% over 1.5 min with a flow
rate of 28 mL/min. Fractions were collected by UV detection at 254
nm or by mass and evaporated using a Genevac EZ-2.
Chiral Methods
Chiral Method: Enantiomeric excess was determined by integration of
peaks that were separated on a Diacel Chiralpak IA, 4.6.times.250
mm column, 5 .mu.m particle size. The solvents used were "Solvent
A": 4:1 (hexanes with 0.2% TFA):DCM, and "Solvent B": EtOH. The
flow rate was held at 1.0 mL/min with the following gradient:
Increase Solvent B from 2-10% over 30 min, hold Solvent B at 10%
for 15 min.
Chiral Method 2: Enantiomeric excess was determined by integration
of peaks that were separated on a Daicel Chiralpak IC,
4.6.times.250 mm column, 5 .mu.m particle size running an isocratic
mixture of 76% (0.2% TFA in iso-hexanes), 19% DCM and 5% EtOH at a
flow rate of 1.5 mL/min.
Chiral Preparative HPLC: This was carried out using a Gilson
preparative HPLC system equipped with a Daicel Chiralpak IC column,
20.times.250 mm column, 5 .mu.m particle size running an isocratic
mixture of mobile phase A (60% (0.2% TFA in iso-hexanes) and 40%
DCM) at 15 mL/min and at-column-dilution with mobile phase B (EtOH)
at 1.5 mL/min. Fractions were collected by UV detection at 254 nm
and evaporated using a Genevac EZ-2.
Experimental Procedures
General Procedures
General Procedure 1: Preparation of Nitriles.
A stirred a solution of bromide or triflate (1 eq), zinc cyanide (2
eq) and tetrakis (triphenylphosphine) palladium (1-5 mol %) in dry
NMP (0.5-1 M) was degassed with N.sub.2. The reaction was heated to
100.degree. C. for 18 h while stirring under N.sub.2. The reaction
mixture was cooled and poured into water and DCM. The solid
material was removed by filtration and the filtrate was extracted
with water. The organic layer was dried over MgSO.sub.4 and
concentrated. The crude product was purified by chromatography.
General Procedure 2: Preparation of Amidoximes.
To a stirring solution of nitrile (1 eq) in EtOH was added
hydroxylamine (50% solution in H.sub.2O, 5 eq) and TEA (1.1 eq).
The mixture was heated for 2-12 h at 80-85.degree. C. then
concentrated. The resulting solid was dissolved in EA, washed with
water, then dried with Na.sub.2SO.sub.4, concentrated and used
without further purification. Alternatively, to a stirring solution
of nitrile (1 eq) and TEA (2-3 eq) in DMF or EtOH was added
hydroxylamine hydrochloride (2-3 eq). The mixture was stirred at
room temperature up to 80.degree. C. for up to 24 h then
concentrated. The resulting solid was dissolved in EA or DCM,
washed with water or brine, then dried with Na.sub.2SO.sub.4,
concentrated, and used without further purification.
General Procedure 3: Preparation of Amides Via Acid Chlorides.
To a solution of amine (1 eq) and base (either DIEA or TEA) (2-3
eq) in DCM (0.06-0.30 M) was treated with the appropriate acid
chloride (1.0-1.5 eq). The reaction mixture was stirred until the
reaction was complete. The reaction was diluted with DCM and washed
with saturated aqueous NaHCO.sub.3. The organic layer was dried
over MgSO.sub.4 and concentrated. The product was purified by
chromatography or preparative HPLC. Alternatively, the crude
reaction mixture can be carried on to the next step without further
purification.
General Procedure 4: Hydrolysis of Esters to Acids.
To a stirring solution of ester (1 eq) in THF or dioxane and water,
was added NaOH or LiOH (1-3 eq). The reaction mixture was stirred
at up to 60.degree. C. for up to 18 h. The reaction mixture was
neutralized with AcOH or HCl and either diluted with water or
concentrated. If the reaction mixture was diluted with water, then
HCl was added to acidify the reaction mixture to a pH of
approximately 2. The resulting precipitate was isolated by
filtration to yield product which can be purified by
chromatography, preparative HPLC, or used without purification. If
the reaction mixture was concentrated, the crude material was
diluted with DCM or EA and washed with brine. The organic layer was
concentrated and purified by chromatography or preparative HPLC to
give final product. Alternatively, the crude material can be
carried forward without purification.
Dealkylation of methyl esters: A stirred solution of methyl ester
(1 eq) in refluxing pyridine (0.03-0.17 M) was treated with LiI (10
eq). Heating was continued until the reaction was adjudged complete
by LCMS analysis. The mixture was allowed to cool then acidified
with HCl and extracted with EA or DCM. The organic layer was dried
over MgSO.sub.4 and evaporated and the residue purified by
preparative HPLC or column chromatography.
General Procedure 5: Preparation of Oxadiazoles Via Acids or Acid
Chlorides.
Oxadiazoles Via Acids:
To a solution of acid (1 eq) in DMF was added HOBt (2 eq) and EDC
(2 eq). After stirring for 2 h, amidoxime (2 eq) was added and the
mixture was stirred at room temperature for up to 12 h. The
reaction mixture was then heated to 100.degree. C. for up to 12 h.
Alternatively, after stirring at room temperature, the reaction
mixture was diluted with DCM, washed with NaHCO.sub.3, then dried
with Na.sub.2SO.sub.4 and concentrated. The resulting residue was
dissolved in EtOH and heated in a microwave for 35 min at
110.degree. C. The solvent was removed and the final product was
purified by preparative HPLC.
Oxadiazoles via Acid Chlorides: To synthesize oxadiazoles via acid
chlorides, dioxanes and DIEA (1.5 eq) were added to a stirred
solution of amidoxime (1 eq) followed by an acid chloride (1.1 eq).
The reaction mixture was stirred at room temperature for 30 min
then at 120.degree. C. for up to 6 h. The reaction mixture was
allowed to cool to room temperature, diluted with EA and washed
with brine. The organics were concentrated and the residue purified
by chromatography.
General Procedure 6: Removal of Tert-Butyl Carbamate.
A solution of the tert-butyl carbamate (1 eq) in DCM (0.06 M) was
treated with TFA (0.16-0.33 M) or HCl in ether (0.16-0.33 M). The
reaction mixture was stirred at either room temperature or
30.degree. C. until complete. The solvent was removed and the
product was purified by chromatography or preparative HPLC.
General Procedure 7: Preparation of Amides Via Peptide
Coupling.
A solution of amine (1.0 eq) and base (DIEA, TEA or NMM) (0-3.0 eq)
in DCM or DMF (0.08-0.10 M) was treated with the appropriate
carboxylic acid (1.0-1.5 eq). To this mixture was added the
coupling reagent. The coupling reagent could be HATU (1.05-2.5 eq)
optionally with DMAP (0.01-1 eq), EDC (1.5 eq) with HOBt (1.5 eq)
or DMAP (2.0 eq), DCC (1.1 eq) with HOBt (1.1 eq) or DCC (1.5 eq)
with DMAP (2.0 eq). The reaction mixture was stirred until the
reaction was complete. The reaction was diluted with EA and washed
with saturated aqueous NaHCO.sub.3. The organic layer was dried
over MgSO.sub.4 and concentrated. The product was purified by
chromatography or alternatively can be carried on to the next step
without further purification.
General Procedure 8: Deprotection of Esters to Acids, Deprotection
of Boc-Amines, and/or Protodesilylation of Protected Alcohols
A solution of the tert-butyl ester or Boc-amine (1.00 eq) in DCM
(0.06 M) was treated with TFA (0.16-0.33 M) or 1-4 N HCl in ether
or dioxane (10.0-20.0 eq). The reaction mixture was stirred at
either room temperature or 30.degree. C. until complete. The
solvent was removed and the product was purified by chromatography
or preparative HPLC. This procedure was also applicable for
protodesilylation of tert-butyl dimethylsilyl protected
alcohols.
A solution of the methyl ester (1.00 eq) in dioxane (0.04-0.08 M)
was treated with 1-6N aqueous HCl (10-100 eq). The reaction mixture
was stirred at either room temperature or 30.degree. C. until
complete. The solvent was removed and the product was purified by
chromatography or preparative HPLC.
General Procedure 9: Formation of Triflate.
A solution of the phenol (1.0 eq) in DCM (0.25 M) was treated with
1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide
(1.1 eq). The reaction mixture was stirred at room temperature
until complete. The reaction was stirred with water and saturated
aqueous NaHCO.sub.3. The organic layers was dried and concentrated.
The material was purified by chromatography or alternatively used
without purification.
General Procedure 10: Palladium-catalyzed Coupling Reactions.
A solution of boronic acid or boronate ester (1.0-1.3 eq), halide
(1.0-1.3 eq), sodium bicarbonate or sodium carbonate decahydrate
(2.0-2.5 eq), and
dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) or
Pd(dppf)Cl.sub.2 were combined in THF, acetonitrile, or dioxane
(0.1-0.2 M) and water (0.25-0.50 M). The reaction was heated at 80
to 100.degree. C. until complete. The reaction was diluted with EA
and washed with saturated aqueous NaHCO.sub.3. The organic layer
was dried over MgSO.sub.4 and concentrated. The product can be
purified by chromatography, preparative HPLC, or carried on to the
next step without further purification.
General Procedure 11: Palladium-catalyzed Aryl Amidation.
A solution of aryl bromide or triflate (1.00 eq), sodium
tert-butoxide or cesium carbonate (1-2 eq) and amine (1.0-1.5 eq)
in dioxane or THF (0.05M) was degassed using N.sub.2 bubbling for
10 min. Pd.sub.2(dba).sub.3 (0.10 eq) and
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (0.15 eq)
are added and the reaction mixture was heated for 45-60 min at
100-120.degree. C. in a microwave reactor or up to 80.degree. C.
with conventional heating for up to 18 h. The reaction was diluted
with EA and washed with saturated aqueous NaHCO.sub.3. The organic
layer was dried over Na.sub.2SO.sub.4 and concentrated. The product
can be purified by chromatography, preparative HPLC, or carried on
to the next step without further purification.
General Procedure 12: Alklation of Phenols, Imidazoles, Lactams and
Amines.
To a solution of a phenolic intermediate in DMF, acetone or ACN
(0.1 M) were added the appropriate bromoalkane (1.5 eq) or tosylate
and either Cs.sub.2CO.sub.3 (1.5-2.0 eq) or K.sub.2CO.sub.3
(1.5-2.0 eq). The reaction mixture was heated at 40-70.degree. C.
for up to 18 h, then diluted with DCM and washed with H.sub.2O. The
organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The
product can be purified by chromatography, preparative HPLC, or
carried on to the next step without further purification.
General Procedure 13: Sulfonate or Sulfonamide Formation.
To a solution of alcohol or amine in DCM (0.02 M) was added the
sulfonyl chloride (2 eq) and triethylamine (3 eq). The reaction was
stirred at room temperature until complete. The reaction was
diluted with DCM and washed with saturated aqueous NaHCO.sub.3. The
organic layer was dried over MgSO.sub.4 and concentrated. The
product can be purified by chromatography, preparative HPLC, or
carried on to the next step without further purification.
General Procedure 14: Reduction of Aryl Nitro to an Aryl Amine.
To a stirring solution of aryl nitro (1 eq) in THF purged with
N.sub.2 was added palladium on carbon. The reaction mixture was
subjected to an H.sub.2 atmosphere for up to 4 h. The reaction
mixture can be filtered over a pad of celite and solvent
concentrated. The crude material was carried forward without
further purification.
General Procedure 15: Preparation of a Secondary or Tertiary Amine
Via Reductive Amination.
To a stirring solution of aldehyde or ketone (0.9-1.0 eq) in DCM or
1,2-dichloroethane or THF was added an amine (0.9-1.1 eq). After
stirring at room temperature for up to 2 h, one drop of acetic acid
(optional) was added followed by sodium triacetoxyborohydride
(1.5-2.0 eq) and the reaction mixture was stirred overnight. In
some cases it is necessary to filter the reaction mixture,
redissolve and add additional reducing agent to drive the reaction
to completion. The crude reaction mixture was quenched with
NaHCO.sub.3 and stirred for 5 min. The aqueous layer was extracted
with DCM and the organic layer was dried over MgSO.sub.4 and
concentrated. The final product was isolated by chromatography.
General Procedure 16: Preparation of 2-Iodopyrimidines
To a stirring solution of a 2-chloro pyrimidine (1 eq) in 57%
aqueous hydrogen iodide (1 mL) was added sodium iodide (2 eq). The
reaction mixture was stirred at ambient temperature until the
starting material was consumed. The reaction mixture was quenched
with NaHCO.sub.3 (5 mL) then extracted with EA (3.times.5 mL). The
combined organic layer was washed with brine (10 mL), dried over
MgSO.sub.4 and concentrated. The crude product was used in the
subsequent step without purification.
General Procedure 17. Preparation of 2-Iodopyridines
To a stirring solution of a 2-chloropyridine (1 eq) in acetonitrile
(2 mL) was added sodium iodide (6 eq). The reaction mixture was
heated to 40.degree. C. and acetyl chloride (0.6 eq) was added. The
reaction mixture was stirred until the staring material was
consumed. The reaction was quenched with NaHCO.sub.3 (5 mL) and
extracted with EA (3.times.5 mL). The combined organic layer was
washed with brine (10 mL), dried over MgSO.sub.4 and concentrated.
The crude product was used in the subsequent step without
purification.
General Procedure 18: Hydrogenation to Reduce an Alkene or
Deprotect Cbz-protected Amine, Benzyl Esters, or Benzyl Amines
Conventional Hydrogenations: To a stirring solution of alkene,
Cbz-protected amine, benzyl protected ester, or benzyl protected
amine (1.0 eq) in EA, THF, EtOH, or MeOH (0.01-0.05 M) was added
Pd/C and the reaction was stirred under hydrogen until complete.
The catalyst was filtered and the solvent was removed. The product
was purified by chromatography or alternatively can be carried onto
the next step without further purification.
Hydrogenation using H-cube: A solution of alkene, Cbz-protected
amine, benzyl protected ester, or benzyl protected amine (1.0 eq)
in dioxane or THF (0.01-0.03 M) was passed over a 10% Pd/C CatCart
in a Thales Nanotechnology H-Cube reactor at 1 mL/min. The solvent
was evaporated and the product was carried to the next step without
further purification
General Procedure 19: Preparation of Aryl-Acids from Aryl
Bromides
To a stirring solution of oven-dried lithium formate (3 eq) and
DIEA (2 eq) under N.sub.2 in DMF (0.1 M) was added acetic anhydride
(2eq). After 30 minutes, the mixture was degassed by N.sub.2
bubbling for 15 min and then added to a similarly degassed solution
of aryl bromide (1 eq) and PdCl.sub.2 (dppf) (0.1 eq) in DMF (0.1
M). The resulting mixture was heated in a microwave reactor for 1
hr at 120.degree. C. After cooling, the mixture was diluted with
DCM and washed with water. The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated. The resulting crude material
was purified by chromatography.
General Procedure 20: Alkylation of Phenols Via Mitsunobu
Condensation of Alcohols
To a stirring solution of phenol (1 eq) in THF was added an alcohol
(1.1 eq), triphenyl phospine (1.1 eq) and diisopropyl
azodicarboxylate (1.1 eq). The reaction mixture was stirred
overnight, concentrated and purified by preparative HPLC.
General Procedure 21: Palladium Catalyzed Coupling (Sonogashira
Coupling)
To a suspension of alkyne (1 eq), iodide (1.2 eq), and diethylamine
(5 eq) in anhydrous diethyl ether (0.2 M) was added CuI (0.1 eq)
followed by Pd(PPh.sub.3).sub.2Cl.sub.2 (0.05 eq). The reaction
mixture was stirred under N.sub.2 at room temperature for 24 h. The
reaction mixture was diluted with ethyl acetate, washed with
saturated aqueous ammonium chloride then brine, and dried over
MgSO.sub.4. The crude product was purified by silica gel column
chromatography.
General Procedure 22: Methyl or Ethyl Ester Formation
To a stirring suspension of amino acid (1 eq) in MeOH or EtOH (0.5
M) was added TMS-Cl (4-10 eq) and the mixture stirred at ambient
temperature (RT-reflux) for 4-24 h. The reaction mixture was cooled
and concentrated/purified to yield desired ester.
General Procedure 23: Boc Protection.
To a stirring suspension of amino ester (1 eq) in DCM (0.25 M) at
0.degree. C. was added DIEA (1.1 eq) and di-tert-butyl dicarbonate
(1.2 eq). The reaction was stirred for between 4-24 h before being
washed with water and dried over MgSO.sub.4. The final product was
isolated by chromatography.
General Procedure 24: Swern Oxidation
To a stirring solution of oxalyl chloride (1.6 eq) in DCM (0.17 M)
at -78.degree. C. was added DMSO (3.2 eq) and the reaction stirred
for 10 mins. A solution of alcohol (1 eq) in DCM was then added by
cannula and the reaction stirred at -78.degree. C. for 2 h before
the addition of DIEA (5 eq). The solution was warmed to 0.degree.
C., stirred for an additional 60 minutes then washed with saturated
ammonium chloride solution. The organic layer was dried over
MgSO.sub.4 and concentrated. The crude product was purified by
column chromatography or used directly
General Procedure 25: Sodium Borohydride Reduction
To a stirring solution of ketone (1 eq) in MeOH (0.17 M) at
-78.degree. C. was added NaBH.sub.4 (0.7 eq). The reaction was
stirred for 30 min before the addition of saturated ammonium
chloride solution and warming to room temperature. MeOH was removed
by reduced pressure distillation and the aqueous extracted with
DCM. The combined organic extracts were dried over MgSO.sub.4 and
concentrated. The final product was isolated by chromatography.
General Procedure 26: t-Butyl Ester Formation
To a stirring suspension of acid (1 eq) in DME (0.5 mL) at
-10.degree. C. was added concentrated sulfuric acid (6 eq) followed
by 2-methylprop-1-ene (100 eq). The mixture was sealed in a
pressure vessel and stirred at 0.degree. C. for 18 h. The reaction
was then cooled to -10.degree. C. and the vessel opened. The
reaction was warmed to RT over 30 minutes over which time all the
isobutylene evaporated. The reaction was diluted with EA and
saturated sodium bicarbonate was added to pH8 with vigorous
stirring. The phases were separated and the aqueous re-extracted
with EA. The combined organic extracts were dried over MgSO.sub.4
and concentrated. The final product was isolated by
chromatography.
General Procedure 27: Boronic Acid Synthesis.
To a stirring solution of bromide (1 eq) in THF (0.14 M) at
-78.degree. C. was added butyllithium (1.5 eq) and the solution
stirred for 20 mins. Trimethyl borate (1.1 eq) was added and the
reaction warmed to RT. The mixture was quenched with water and
extracted with ethyl acetate. The combined organics were washed
successively with 1 N HCl and saturated brine (50 ml), dried over
MgSO.sub.4 and concentrated. The final product was isolated by
chromatography.
General Procedure 28: Hydrazide Formation
To a stirring solution of methyl ester (1 eq) in 1:1 THF:EtOH (0.05
M) was added hydrazine hydrate (10 eq) and the solution stirred for
16 h. The product was precipitated with water and isolated by
filtration.
General Procedure 29: Oxadiazole Thione Formation
To a stirring solution of hydrazide (1 eq) and DIEA in THF (0.027
M) was added thiocarbonyldiimidazole (1.2 eq) and the solution
stirred for 2 h. The mixture was warmed to 45.degree. C. for a
further 1 h then quenched with aqueous AcOH and extracted with DCM.
The organics were dried through a hydrophobic frit and
concentrated. The final product was isolated by chromatography.
General Procedure 30: Amino Alcohol Synthesis.
To a stirring solution of diisopropylamine (1.15 eq) in THF (0.34
M) at 0.degree. C. was added butyllithium (1.1 eq of a 2.4 M
solution in hexanes). After 30 mins, the mixture was cooled to
-78.degree. C. and treated with tert-butyl
2-((diphenylmethylene)amino)acetate (1 eq). After 30 mins,
chlorotrimethylsilane (3 eq) was added and the mixture allowed to
warm to room temperature. The resulting solution was added to a
stirring solution of aldehyde (1 eq) and zinc chloride (0.05 eq of
a 0.5 M solution in diethyl ether) in THF (0.36 M). After 16 h, the
mixture was quenched with 10% aqueous citric acid and stirred for a
further 16 h. The product was isolated by direct
strong-cation-exchange ion-exchange chromatography of the reaction
mixture and used without further purification.
General Procedure 31: Tyrosine Analog by Negishi Coupling
To a stirring solution of zinc (3 eq) in DMF (1-1.4 M) was added
iodine (1 eq). When the colour had been discharged, (R)-methyl
2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (1 eq) and
additional iodine (0.15 eq) were charged. After 30 mins, aryl
halide (1 eq), Pd.sub.2dba.sub.3 (2.5 mol %) and S-Phos (5 mol %)
were charged and the mixture stirred at room temperature or heated
to 50.degree. C. for 2-16 h. The product was directly isolated by
column chromatography.
General Procedure 32: Stille Coupling
To a stirring solution of aryl halide (1 eq) and stannane (1 eq) in
DMF (0.22 M) was added cesium fluoride (2 eq), copper iodide (1 eq)
and Pd(PPh.sub.3).sub.4 (7 mol %). The mixture was heated at
50.degree. C. for 16 h then diluted with THF and EA, filtered
through Celite and evaporated. The product was isolated by column
chromatography. Alternatively, a solution of aryl halide (1 eq) and
stannane (1 eq) in DMF (0.1 M) was treated with
PdCl.sub.2(PPh.sub.3).sub.4 (10 mol %) and heated to 80-100.degree.
C. for 3-6 h. The product was directly isolated by column
chromatograophy.
General Procedure 33: Tyrosine Analogue by HWE
To a stirring solution of aldehyde (1 eq) and methyl
2-((tert-butoxycarbonyl)amino)-2-(dimethoxyphosphoryl)acetate in
DCM (0.27 M) was added dropwise DBU (2 eq). After 16 h, the mixture
was washed successively with NaHCO.sub.3 and aqueous AcOH, dried
over MgSO.sub.4 and evaporated. The product was isolated by column
chromatography.
General Procedure 34: Radical Bromination
To a stirring solution of substrate (1 eq) and N-bromosuccinimide
(1.1 eq) in carbon tetrachloride (0.29 M) was added
azobis-iso-butyronitrile (0.1 eq) and the mixture heated under
reflux. After 2 h, the mixture was allowed to cool, filtered
through cotton wool and evaporated. The product was isolated by
column chromatography.
General Procedure 35: Tyrosine Analog by Alkylation
To a stirring solution of tert-butyl
2-((diphenylmethylene)amino)acetate (1 eq) in THF (0.16 M) at
0.degree. C. was added sodium hydride (1.2 eq). After 30 mins,
bromide (1 eq) was added and the mixture warmed to room temperature
over 1 h. The mixture was quenched into water and extracted with
EA. The combined organic extracts were dried over MgSO.sub.4 and
solvents evaporated. The product was isolated by column
chromatography.
General Procedure 36: Ullmann Coupling
To a stirring solution of aryl bromide (1 eq) and alcohol (10 eq)
in toluene (0.1 M) was added copper iodide (0.1 eq),
1,10-phenanthroline (0.2 eq) and cesium carbonate (1.5 eq). The
mixture was heated at 110.degree. C. for 16 h then quenched with
aqueous acetic acid and extracted with EA. The combined organic
extracts were dried over MgSO.sub.4 and solvents evaporated. The
product was isolated by column chromatography.
General Procedure 37: Ketone Coupling
To a stirring solution of aryl bromide (1 eq) in dioxane (0.06 M)
was added ketone (1-2 eq), tosylhydrazine (1-2 eq), lithium
tert-butoxide (3-5.5 eq), Pd.sub.2dba.sub.3 (2 mol %) and Xphos (8
mol %). The mixture was heated to 100.degree. C. for 16 h then
quenched with aqueous acetic acid and extracted with DCM. The
combined organic extracts were dried over MgSO.sub.4 and solvents
evaporated. The product was isolated by column chromatography or
preparative HPLC.
General Procedure 38: Organometallic Addition to Ketone
To a stirring solution of organometallic reagent (1.1 eq) in THF
(0.4 M) was added a solution of ketone (1 eq) in THF (1.2 M) at
-5.degree. C. After 1 h, the mixture was quenched with aqueous
ammonium chloride and extracted with DCM. The combined organic
extracts were dried over MgSO.sub.4 and solvents evaporated. The
product was isolated by column chromatography.
General Procedure 39: Elimination of an Alcohol to Alkene
A solution of the alcohol (1 eq) in DCM (0.06-1 M) was treated with
TFA (0.16-10 M). The reaction mixture was stirred at either room
temperature or 30.degree. C. until complete. The solvent was
removed and the product was purified by chromatography or
preparative HPLC.
General Procedure 40: Acidic Deprotection of Cbz-amine
A solution of Cbz-amine (1 eq) in DCM (0.03 M) was treated with
boron tribromide (2 eq). After 2 h, the mixture was quenched with
MeOH and basified with methanolic ammonia. The solvents were
evaporated and the product purified by column chromatography.
Synthesis of Representative Compounds
4-(heptyloxy)benzonitrile
##STR00130##
Prepared using General Procedure 1: A stirred a solution of
1-bromo-4-(heptyloxy)benzene (2.0 g, 7.37 mmol), zinc cyanide (1.73
g, 14.74 mmol) and tetrakis (triphenylphosphine) palladium (76.12
mg, 0.07 mol) in dry NMP (20 mL) was degassed with N.sub.2. The
reaction was heated to 100.degree. C. for 18 h while stirring under
nitrogen. The reaction mixture was cooled and poured into water
(100 mL) and DCM (20 mL). The solid material was removed by
filtration and the filtrate was extracted with water (3.times.20
mL). The organic layer was dried over MgSO.sub.4 and concentrated.
The crude product was purified by chromatography (EA/hexanes) to
afford 1.15 g (73%) of 4-(heptyloxy)benzonitrile as a light yellow
solid. LCMS-ESI (m/z) calculated for C.sub.14H.sub.19NO: 217.1;
found 218.1 [M+H].sup.+, t.sub.R=11.14 min (Method 2). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.64-7.50 (m, 2H), 7.05-6.83 (m, 2H),
3.99 (t, J=6.5 Hz, 2H), 1.89-1.69 (m, 2H), 1.58-1.12 (m, 8H), 0.90
(dd, J=9.1, 4.5 Hz, 3H). .sup.13C NMR (101 MHz CDCl.sub.3) .delta.
162.47, 133.91, 132.78, 132.12, 129.13, 119.31, 115.18, 103.58,
68.41, 31.73, 28.98, 25.89, 22.58, 14.07.
(Z)-4-(heptyloxy)-N'-hydroxybenzimidamide
##STR00131##
Prepared using General Procedure 2: To a stirring solution of
4-(heptyloxy)benzonitrile (1.0 g, 4.6 mmol) in EtOH (15 mL) were
added hydroxylamine hydrochloride (0.96 g, 13.8 mmol) and TEA (2.22
g, 23.0 mmol). The reaction was heated to 85.degree. C. for 2 h.
The solvent was removed under reduced pressure and the residue was
diluted with water (20 mL) and extracted with DCM (3.times.10 mL).
The combined organic layers were concentrated under reduced
pressure. The crude material was crystallized from isopropanol (20
mL) to afford 1.05 g (91%) of
(Z)-4-(heptyloxy)-N'-hydroxybenzimidamide as a white solid.
LCMS-ESI (m/z) calculated for C.sub.14H.sub.22N.sub.2O.sub.2:
250.2; found 251.3 [M+H].sup.+, t.sub.R=1.70 min (Method 1).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.45 (s, 1H), 7.59 (d,
J=8.6 Hz, 2H), 6.93 (t, J=14.7 Hz, 2H), 5.82-5.48 (m, 2H), 3.97 (t,
J=6.5 Hz, 2H), 1.83-1.55 (m, 2H), 1.56-1.05 (m, 8H), 0.87 (t, J=6.7
Hz, 3H). .sup.13C NMR (101 MHz CDCl.sub.3) .delta. 159.19, 150.53,
126.64, 125.55, 113.87, 67.40, 31.21, 28.62, 28.40, 25.44, 22.02,
13.92.
(S)-methyl 4-(2-amino-3-methoxy-3-oxopropyl)benzoate
##STR00132##
To a solution of
(S)-2-amino-3-(4-(tert-butoxycarbonyl)phenyl)propanoic acid (500.0
mg, 1.88 mmol) in MeOH (20 mL) at 0.degree. C. was slowly added
thionyl chloride (447.64 mg, 3.77 mmol). The reaction was stirred
for 1 h at 0.degree. C. then warmed to room temperature and stirred
for 1 h. The solvent was removed under reduced pressure. The
reaction mixture was washed with saturated aqueous NaHCO.sub.3 (20
ml) and extracted with DCM (3.times.10 ml). The organic layer was
dried over MgSO.sub.4 and concentrated. The crude product was
purified by chromatography (EA/hexanes) to afford 425 mg (95%) of
(S)-methyl 4-(2-amino-3-methoxy-3-oxopropyl)benzoate as the HCl
salt. LCMS-ESI (m/z) calculated for C.sub.12H.sub.15NO.sub.4:
237.1; found 238.0 [M+H].sup.+, t.sub.R=1.01 min (Method 1).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.55 (s, 3H), 7.94 (d,
J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 4.37 (t, J=6.8 Hz, 1H), 3.86
(s, 3H), 3.68 (s, 3H), 3.20 (dd, J=11.8, 6.8 Hz, 2H).
(S)-methyl
4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate
##STR00133##
Prepared using General Procedure 3: To the solution of (S)-methyl
4-(2-amino-3-methoxy-3-oxopropyl)benzoate (425.0 mg, 1.79 mmol) in
DCM (10 mL) and DIEA (463.0 mg, 3.58 mmol) was added
4-(tert-butyl)benzoyl chloride (556.6 mg, 2.83 mmol) at room
temperature. The reaction was stirred for 2 h and the reaction was
partitioned between DCM and saturated aqueous NaHCO.sub.3. The
organic layer was dried over MgSO.sub.4 and concentrated. The crude
product was purified by chromatography (EA/hexanes) to afford 317
mg (45%) of (S)-methyl
4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate.
LCMS-ESI (m/z) calculated for C.sub.23H.sub.27NO.sub.5: 397.2;
found 398.1 [M+H].sup.+, t.sub.R=2.31 min (Method 1). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.97-7.75 (m, 2H), 7.67-7.51 (m, 2H),
7.46-7.26 (m, 2H), 7.14 (d, J=8.3 Hz, 2H), 6.60 (d, J=7.4 Hz, 1H),
5.03 (dt, J=7.4, 5.7 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H), 3.28 (dd,
J=13.7, 5.8 Hz, 1H), 3.18 (dd, J=13.7, 5.5 Hz, 1H), 1.24 (s,
9H).
(S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic
acid (INT-1)
##STR00134##
Prepared using General Procedure 4: To a stirred solution of
(S)-methyl
4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate
(316.6 mg, 0.79 mmol) in dioxane (15 mL) and water (1 mL) at
0.degree. C. was added lithium hydroxide monohydrate (93.52 mg,
2.23 mmol). After 2 h, the solution was neutralized with 1 M HCl to
pH 7.0. The mixture was partitioned between DCM (15 mL) and
saturated aqueous NaHCO.sub.3 (10 mL). The organic layer was washed
with saturated aqueous NaHCO.sub.3 (3.times.10 mL) and brine (10
mL). The organic layer was dried over MgSO.sub.4 and concentrated
to afford 208 mg (69%) of
(S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic
acid (INT-1). LCMS-ESI (m/z) calculated for
C.sub.22H.sub.25NO.sub.5: 383.2; found 384.1 [M+H].sup.+,
t.sub.R=2.13 min. (Method 1). .sup.1H NMR (400 MHz, DMSO) .delta.
12.86 (s, 1H), 8.80 (d, J=8.0 Hz, 1H), 7.87-7.78 (m, 2H), 7.75-7.65
(m, 2H), 7.50-7.35 (m, 4H), 4.72 (ddd, J=10.3, 8.0, 5.1 Hz, 1H),
3.65 (s, 3H), 3.28-3.05 (m, 2H), 1.29 (s, 9H). .sup.13C NMR (101
MHz, DMSO) .delta. 173.00, 167.21, 166.29, 154.39, 143.10, 130.85,
129.34, 129.27, 129.21, 129.03, 127.21, 125.39, 125.10, 53.75,
52.04, 34.64, 30.92, 30.88.
(S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,
2,4-oxadiazol-5-yl)phenyl)propanoate
##STR00135##
Prepared using General Procedure 5: To a solution of
(S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic
acid (INT-1) (10.0 mg, 0.026 mmol) in anhydrous DMF (1 mL) was
added HOBt (5.27 mg, 0.39 mmol) and EDC (7.48 mg, 0.39 mmol). After
stirring for 2 h, (Z)-4-(heptyloxy)-N'-hydroxybenzimidamide (9.76
mg, 0.39 mmol) was added. The reaction mixture was stirred at room
temperature for 2 h, partitioned between saturated aqueous
NaHCO.sub.3 (5 ml) and EA (5 mL), and concentrated under reduced
pressure to afford the intermediate (S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(((4-(heptyloxy)benzimidamido)oxy)carbon-
yl)phenyl)propanoate. The intermediate was dissolved in DMF (1 mL)
and heated to 100.degree. C. for 18 h. The reaction mixture was
cooled to room temperature and partitioned between EA (5 mL) and
saturated aqueous NaHCO.sub.3 (5 mL). The organic layer was
extracted with water (2.times.5 mL) and brine (5 mL). The organic
layer was dried over MgSO.sub.4 and concentrated. The brown oil was
purified by preparative HPLC to afford 4.5 mg (29%) of (S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-
-5-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for
C.sub.36H.sub.43N.sub.3O.sub.5: 597.3; no m/z observed,
t.sub.R=12.75 min (Method 2). .sup.1H NMR (400 MHz, DMSO) .delta.
8.85 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.3 Hz, 2H), 8.00 (d, J=8.9 Hz,
2H), 7.74 (d, J=8.5 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.6
Hz, 2H), 7.12 (d, J=8.9 Hz, 2H), 4.87-4.56 (m, 1H), 4.06 (t, J=6.5
Hz, 2H), 3.67 (s, 3H), 3.32-3.13 (m, 4H), 1.74 (dd, J=14.2, 6.5 Hz,
2H), 1.51-1.37 (m, 2H), 1.33 (s, 4H), 1.26 (d, J=20.2 Hz, 9H), 0.88
(t, J=6.9 Hz, 3H). .sup.13C NMR (101 MHz, DMSO) .delta. 175.00,
171.91, 167.89, 166.27, 161.21, 154.37, 143.68, 130.78, 130.30,
128.76, 127.80, 127.18, 125.07, 121.69, 118.21, 115.07, 67.72,
53.61, 52.05, 36.15, 34.60, 31.20, 30.87, 28.54, 28.39, 25.40,
22.02, 13.93.
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadia-
zol-5-yl)phenyl)propanoic acid (Compound 1)
##STR00136##
Prepared using General Procedure 4: To a solution of (S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-
-5-yl)phenyl)propanoate (4.52 mg, 0.008 mmol) in MeOH (2 mL) was
added of 1 N NaOH (1 mL). The reaction mixture was stirred at
50.degree. C. for 3 h. The resulting mixture was purified by
preparative HPLC to afford 0.36 mg (8%) of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(3-(4-(heptyloxy)phenyl)-1,2,4-oxadi-
azol-5-yl)phenyl)propanoic acid (Compound 1). LCMS-ESI (m/z)
calculated for C.sub.35H.sub.41N.sub.3O.sub.5: 583.7; no m/z
observed, t.sub.R=12.59 min (Method 2).
(S)-methyl 2-amino-3-(4-cyanophenyl)propanoate
##STR00137##
To a solution of
(S)-2-((tert-butoxycarbonyl)amino)-3-(4-cyanophenyl)propanoic acid
(1.0 g, 3.44 mmol) in MeOH (20 mL) at 0.degree. C. was slowly added
thionyl chloride (818.1 mg, 6.89 mmol) over 1 h. The reaction was
warmed to room temperature and stirred for 1 h. The solvent was
removed under reduced pressure. The reaction mixture was washed
with saturated aqueous NaHCO.sub.3 (20 ml) and extracted with DCM
(3.times.10 ml). The organic layer was dried over MgSO.sub.4 and
concentrated. The crude product was purified by chromatography
(EA/hexanes) to afford 789 mg (97%) of (S)-methyl
2-amino-3-(4-cyanophenyl)propanoate as the HCl salt. LCMS-ESI (M/z)
calculated for C.sub.11H.sub.12N.sub.2O.sub.2; 204.1; found 205.0
[M+H].sup.+, t.sub.R=3.25 min (Method 1). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.69 (s, 3H), 7.83 (d, J=8.3 Hz, 2H), 7.51 (t,
J=8.8 Hz, 2H), 4.37 (t, J=6.7 Hz, 1H), 3.68 (s, 3H), 3.23 (qd,
J=14.4, 7.7 Hz, 2H).
(S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-cyanophenyl)propanoate
##STR00138##
Prepared using General Procedure 3: To the solution of (S)-methyl
2-amino-3-(4-cyanophenyl)propanoate (789.2 mg, 3.32 mmol) in DCM
(15 mL) and DIEA (1.29 g, 9.96 mmol) was added
4-(tert-butyl)benzoyl chloride (981.3 mg, 4.99 mmol) at room
temperature. The reaction was stirred for 2 h and the reaction was
partitioned between DCM and saturated aqueous NaHCO.sub.3. The
organic layer was dried over MgSO.sub.4 and concentrated. The crude
product was purified by chromatography (EA/hexanes) to afford 1.06
g (88%) of (S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-cyanophenyl)propanoate. LCMS-ESI
(m/z calculated for C.sub.22H.sub.24N.sub.2O.sub.3: 364.2; found
365.3 [M+H].sup.+, t.sub.R=3.55 min (Method 1). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.81 (d, J=8.0 Hz, 1H), 7.85-7.60 (m, 4H),
7.49 (dd, J=15.1, 8.4 Hz, 4H), 4.85-4.60 (m, 1H), 3.65 (s, 3H),
3.30-3.23 (m, 1H), 3.18 (dd, J=13.7, 10.6 Hz, 1H), 1.29 (s,
9H).
(S,Z)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(N'-hydroxycarbamimidoyl)phenyl)propanoa-
te (INT-2)
##STR00139##
Prepared using General Procedure 2: To a stirring solution
(S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-cyanophenyl)propanoate
(1.0 g, 2.74 mmol) in EtOH (15 mL) were added hydroxylamine
hydrochloride (572.2 mg, 8.22 mmol) and TEA (1.38 g, 13.7 mmol).
The reaction was heated to 85.degree. C. for 2 h. The solvent was
removed under reduced pressure and the residue was diluted with
water (20 mL) and extracted with DCM (3.times.10 mL). The combined
organic layers were concentrated under reduced pressure. The crude
material was crystallized from isopropanol (20 mL) to afford 1.04 g
(95%) of (S,Z)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(N'-hydroxycarbamimidoyl)phenyl)propanoa-
te (INT-2) as a white solid. LCMS-ESI (m/z): calcd for:
C.sub.22H.sub.27N.sub.3O.sub.4, 397.2; found 398.1 [M+1].sup.+,
t.sub.R=2.26 min (Method 1). .sup.1H NMR (400 MHz, DMSO) .delta.
10.19 (s, 1H), 9.57 (s, 1H), 8.78 (d, J=7.9 Hz, 1H), 7.74 (d, J=8.4
Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.30 (d,
J=8.3 Hz, 2H), 4.79-4.49 (m, 1H), 3.65 (s, 3H), 3.15 (dt, J=13.6,
6.0 Hz, 2H), 1.75 (d, J=13.6 Hz, 1H), 1.29 (s, 9H).
(S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-
-oxadiazol-3-yl)phenyl)propanoate
##STR00140##
Prepared using General Procedure 5: To a solution of
4-(heptyloxy)benzoic acid (400.0 mg, 1.54 mmol) in anhydrous DMF (6
mL) were added HOBt (312.3 mg, 2.31 mmol) and EDC (442.75 mg, 2.31
mmol). After stirring for 2 h, (S, Z)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)-propanoa-
te (INT-2) (673.3 mg, 1.69 mmol) was added. The reaction mixture
was stirred at room temperature for 2 h, partitioned between
saturated aqueous NaHCO.sub.3 (15 mL) and EA (15 mL), and
concentrated under reduced pressure to afford the intermediate
(S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(N-((4-(heptyloxy)benzoyl)oxy)carbamimid-
oyl)phenyl)propanoate. The intermediate was dissolved in DMF (10
mL) and heated to 100.degree. C. for 18 h. The reaction mixture was
cooled to room temperature and partitioned between EA (10 mL) and
saturated aqueous NaHCO.sub.3 (50 mL). The organic layer was
extracted with water (2.times.10 mL) and brine (10 mL). The organic
layer was dried over MgSO.sub.4 and concentrated. The brown oil was
purified by chromatography (EA/hexanes) to afford 710 mg (77%) of
(S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-
-3-yl)phenyl)propanoate as a white solid. LCMS-ESI (m/z) calculated
for C.sub.36H.sub.43N.sub.3O.sub.5: 597.3; no m/z observed,
t.sub.R=12.80 min (Method 2). .sup.1H NMR (400 MHz, DMSO) .delta.
8.84 (d, J=8.0 Hz, 1H), 8.08 (t, J=17.2 Hz, 2H), 7.97 (dd, J=18.2,
8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.50 (dd, J=18.6, 8.3 Hz, 4H),
7.18 (d, J=8.9 Hz, 2H), 4.85-4.63 (m, 1H), 4.09 (dd, J=13.8, 7.3
Hz, 2H), 3.67 (s, 3H), 3.24 (ddd, J=23.8, 15.7, 7.3 Hz, 4H), 2.08
(s, 4H), 1.74 (dd, J=14.1, 6.9 Hz, 2H), 1.42 (dd, J=13.6, 6.3 Hz,
2H), 1.30 (d, J=14.5 Hz, 9H), 0.88 (t, J=6.8 Hz, 3H). .sup.13C NMR
(101 MHz, DMSO) .delta. 174.05, 170.87, 133.81, 165.14, 161.43,
153.21, 140.51, 129.70, 128.85, 128.78, 126.06, 125.84, 123.93,
123.39, 114.36, 114.25, 66.86, 52.66, 50.88, 34.32, 33.47, 30.06,
29.74, 27.33, 27.24, 24.23, 20.89, 12.80.
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadia-
zol-3-yl)phenyl)propanoic acid (Compound 2)
##STR00141##
Prepared using General Procedure 4: To a solution of (S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-
-3-yl)phenyl)propanoate (710.0 mg, 1.19 mmol) in MeOH (20 mL) was
added 1 N NaOH (10 mL). The reaction mixture was stirred at
50.degree. C. for 3 h. The resulting mixture was purified by
chromatography (DCM/MeOH) to afford 218 mg (31%) of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadi-
azol-3-yl)phenyl)propanoic acid (Compound 2) as white solid.
LCMS-ESI (m/z) calculated for C.sub.35H.sub.41N.sub.3O.sub.5;
583.3; no m/z observed, t.sub.R=12.16 min (Method 2). .sup.1H NMR
(400 MHz, DMSO) .delta. 8.69 (d, J=8.3 Hz, 1H), 8.16-8.02 (m, 2H),
7.98 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.53 (d, J=8.3 Hz,
2H), 7.47 (d, J=8.5 Hz, 2H), 7.18 (d, J=9.0 Hz, 2H), 4.70 (ddd,
J=10.8, 8.4, 4.5 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H), 3.30 (dd, J=13.8,
4.2 Hz, 1H), 3.17 (dd, J=13.8, 10.7 Hz, 1H), 1.74 (dd, J=14.5, 6.7
Hz, 2H) 1.42 (dd, J=13.8, 6.1 Hz, 2H), 1.37-1.14 (m, 14H), 0.87 (t,
J=6.9 Hz, 3H). .sup.13C NMR (101 MHz, DMSO) .delta. 175.16, 173.00,
167.96, 166.19, 162.55, 154.18, 142.11, 131.08, 129.95, 129.89,
127.14, 126.92, 125.01, 124.39, 115.49, 115.37, 67.98, 53.72,
36.19, 34.58, 31.19, 30.89, 28.46, 28.37, 25.36, 22.01, 13.92.
Compounds 3-11 and 13-61 were prepared from (S,Z)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)propanoat-
e (INT-2) using General Procedures 5 and 4 sequentially.
Compounds 62-66 were prepared from (S,Z)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)propanoat-
e (INT-2) using General Procedures 5, 6, and 4 sequentially.
(S)-2-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxa-
diazol-3-yl)phenyl)propanamido)acetic acid (Compound 67)
##STR00142##
Prepared using General Procedures 7 and 8: To a solution of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadi-
azol-3-yl)phenyl)propanoic acid (Compound 2) (10.0 mg, 0.017 mmol)
in anhydrous DMF (1 mL) was added HOBt (3.52 mg, 0.027 mmol) and
EDCI (4.88 mg, 0.027 mmol) at room temperature. After 2 h,
tert-butyl 2-aminoacetate (3.49 mg, 0.027 mmol) was added and the
reaction mixture stirred at room temperature for 2 h. LCMS analysis
showed complete conversion to the intermediate. The reaction
mixture was partitioned between NaHCO.sub.3 aqueous (5 ml) and DCM
(1 mL), the organic layer was collected and concentrated by vacuum
and then was re-dissolved in 1 mL of DCM and 0.1 mL of TFA. The
mixture was heated to 30.degree. C. for 3 h. The final compound was
purified by HPLC to afford 9.6 mg (88%) of
(S)-2-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-ox-
adiazol-3-yl)phenyl)propanamido)acetic acid (Compound 67). LCMS-ESI
(m/z) calculated for C.sub.37H.sub.44N.sub.4O.sub.6 640.3; no m/z
observed, t.sub.R=11.51 min (Method 2). .sup.1H NMR (400 MHz, DMSO)
.delta.: 8.60 (d, J=8.4 Hz, 1H), 8.47 (t, J=5.7 Hz, 1H), 8.10 (d,
J=8.8 Hz, 2H), 7.96 (d, J=8.2 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.57
(d, J=8.0 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H),
4.83 (d, J=8.1 Hz, 1H), 4.09 (t, J=6.4 Hz, 2H), 3.94-3.69 (m, 2H),
3.34 (s, 2H), 3.26 (d, J=13.5 Hz, 1H), 3.15-3.01 (m, 1H), 1.83-1.65
(m, 2H), 1.50-1.15 (m, 16H), 0.87 (t, J=6.7 Hz, 3H). .sup.13C NMR
(101 MHz, DMSO) .delta.: 175.12, 171.58, 171.13, 167.99, 166.02,
162.54, 154.10, 142.44, 131.16, 130.02, 129.89, 127.23, 126.81,
124.91, 124.25, 115.50, 115.36, 67.97, 54.23, 40.10, 37.12, 34.57,
31.19, 30.88, 28.46, 28.37, 25.36, 22.02, 13.93.
Compound 68 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(piperidin-1-yl)phenyl)-1,2,4--
oxadiazol-3-yl)phenyl)propanoic acid (Compound 5) using General
Procedures 7, and 8 sequentially.
Compound 69 was prepared from (S, Z)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)propanoat-
e (INT-2) using General Procedure 7.
Compound 70 was prepared from (S, Z)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(N-hydroxycarbamimidoyl)phenyl)propanoat-
e (INT-2) using General Procedures 7 and 8 sequentially.
Compounds 71 and 72 were prepared from methyl
2-amino-2-(4-bromophenyl)acetate hydrochloride using General
Procedures 7, 1, 2, 5, and 4 sequentially.
Compounds 73 and 74 were prepared from (S)-methyl
2-amino-4-(4-hydroxyphenyl)butanoate hydrobromide using General
Procedures 7, 9, 1, 2, 5, and 4 sequentially.
Compound 75 was prepared from (S)-methyl
3-amino-4-(4-hydroxyphenyl)butanoate hydrochloride using General
Procedures 7, 9, 1, 2, 5, and 4 sequentially.
4-(heptyloxy)benzohydrazide
##STR00143##
To a stirred solution of 4-(heptyloxy)benzoic acid (679 mg, 2.87
mmol) in THF (5 mL) was added 1,1'-carbonyldiimidazole (559 mg,
3.45 mmol). After stirring at room temperature for 2 h, the
solution was added to a stirred mixture of hydrazine hydrate (0.729
mL, 5.75 mmol) in THF (2 mL) and stirred a further 2 h. The
reaction mixture was poured onto water (20 mL) and stirred for 30
min. The resulting precipitate was collected by filtration, washed
with water (2.times.10 mL) then acetonitrile (3 mL) to afford 0.54
g (71%) of 4-(heptyloxy)benzohydrazide as a white solid. LCMS-ESI
(m/z) calculated for C.sub.14H.sub.22N.sub.2O.sub.2: 250.3 found
251.0 [M+H].sup.+, t.sub.R=2.05 min. (Method 4).
(S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydra-
zine-carbonyl)phenyl)propanoate (INT-3)
##STR00144##
To a stirring solution of
(S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic
acid (INT-1) (260 mg, 0.68 mmol) in THF (5 mL) were added
4-methylmorpholine (0.15 mL, 1.36 mmol) and isobutyl
carbonochloridate (0.09 mL, 0.71 mmol). After stirring at room
temperature for 2 h, 4-(heptyloxy)benzohydrazide (187 mg, 0.75
mmol) was added and stirring continued for another 2 h. The
reaction mixture was poured onto NaHCO.sub.3 (50 mL) and extracted
with DCM (3.times.20 mL). The combined organics were dried over
MgSO.sub.4 and evaporated. The crude product was purified by column
chromatography (100% EA in iso-hexanes) to afford 297 mg (71%) of
(S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazinecarbon-
yl)phenyl)propanoate (INT-3) as an off-white foam. LCMS-ESI (m/z)
calculated for C.sub.36H.sub.45N.sub.3O.sub.6: 615.8 found 616.0
[M+H].sup.+, t.sub.R=2.89 min. (Method 4).
(S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-
-oxadiazol-2-yl)phenyl)propanoate
##STR00145##
To a stirring solution (S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazinecarbon-
yl)phenyl)propanoate (INT-3) (127 mg, 0.21 mmol) and TEA (0.09 mL,
0.62 mmol) in DCM (4 mL) was added
2-chloro-1,3-dimethylimidazolidinium chloride (41.8 mg, 0.25 mmol).
The reaction mixture was stirred at room temperature for 18 h then
warmed to 40.degree. C. for 1 h. The reaction mixture was cooled to
room temperature, diluted with NaHCO.sub.3 (15 mL), shaken, split
through a hydrophobic frit and evaporated to afford 120 mg (95%) of
(S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-oxadiazol-
-2-yl)phenyl)propanoate as a white solid. LCMS-ESI (m/z) calculated
for C.sub.36H.sub.43N.sub.3O.sub.5: 597.8; found 598.0 [M+H].sup.+,
t.sub.R=3.25 min. (Method 4).
Compound 76 was prepared using (S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-oxadiazol-
-2-yl)phenyl)propanoate and General Procedure 4.
2-bromo-1-(4-(heptyloxy)phenyl)ethanone (INT-4)
##STR00146##
To a stirring solution of 1-(4-(heptyloxy)phenyl)ethanone (500 mg,
2.13 mmol) in THF (8.5 mL) under nitrogen was added
phenyltrimethylammonium tribromide (842 mg, 2.24 mmol). The
reaction mixture was stirred at room temperature for 2 h, filtered
under vacuum and the captured solid washed with THF. The combined
liquors were concentrated to afford 919 mg (100%) of
2-bromo-1-(4-(heptyloxy)phenyl)ethanone (INT-4) as a yellow oil.
LCMS-ESI (m/z) calculated for C.sub.15H.sub.21BrO.sub.2: 313.2;
found 313.0 [M+H].sup.+, t.sub.R=2.12 min. (Method 4).
(S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl
4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate
##STR00147##
A solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone (INT-4) (166
mg, 0.45 mmol) in acetonitrile (1 mL) was added to a solution of
(S)-4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoic
acid (INT-1) (190 mg, 0.50 mmol) and TEA (75.0 .mu.l, 0.54 mmol) in
acetonitrile (4 mL). The reaction mixture was stirred at room
temperature for 18 h then poured onto 0.5 M citric acid (30 mL) and
extracted with EA (3.times.25 mL). The combined organics were dried
over MgSO.sub.4, filtered and concentrated. The residue was
triturated with Et.sub.2O (10 mL) and the filtrate concentrated to
afford 159 mg (49%) of (S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl
4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate as a
white solid. LCMS-ESI (m/z) calculated for
C.sub.37H.sub.45NO.sub.7: 615.8; found 616.0 [M+H].sup.+,
t.sub.R=2.76 min. (Method 4).
(S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)oxazol-
-2-yl)phenyl)propanoate
##STR00148##
To boron trifluoride diethyl etherate (33.3 .mu.l, 0.27 mmol) was
added a mixture of acetamide (763 mg, 12.9 mmol) and
(S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl
4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate (159
mg, 0.26 mmol). The reaction mixture was stirred at 140.degree. C.
for 1 h. The reaction mixture was allowed to cool to room
temperature, diluted with EA (15 mL) and extracted with NaHCO.sub.3
(3.times.15 mL) and brine (15 mL). The combined organics were dried
over MgSO.sub.4, filtered and concentrated. The residue was
recrystallized from Et.sub.2O (5 mL), filtered and rinsed with
Et.sub.2O. The filtrate was concentrated to afford 55 mg (16%) of
(S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)oxazol-2-yl)phen-
yl)propanoate as an orange oil. LCMS-ESI (m/z) calculated for
C.sub.37H.sub.44N.sub.2O.sub.5: 596.8; found 597.0 [M+H].sup.+,
t.sub.R=3.11 min. (Method 4).
Compound 77 was prepared from (S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)oxazol-2-yl)phen-
yl)propanoate using General Procedure 4.
2-(4-bromophenyl)-2-oxoethyl 4-(heptyloxy)benzoate
##STR00149##
To stirring mixture of 4-(heptyloxy)benzoic acid (2.0 g, 8.46 mmol)
in acetonitrile (30 mL) at room temperature was added TEA (1.24 mL,
8.87 mmol) drop wise. The reaction mixture was stirred at room
temperature for 1 h, poured onto 0.05 M citric acid (100 mL) and EA
(10 mL) then stirred for 10 min. The precipitate was isolated by
filtration, washed with water (30 mL) and iso-hexanes (2.times.10
mL) then dried in air to afford 3.8 g (98%) of
2-(4-bromophenyl)-2-oxoethyl 4-(heptyloxy)benzoate. LCMS-ESI (m/z)
calculated for C.sub.22H.sub.25BrO.sub.4: 433.3; found 455.0/457.0
[M+Na].sup.+, t.sub.R=3.21 min. (Method 4).
4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)oxazole
##STR00150##
To boron trifluoride etherate (0.322 mL, 2.5 mmol) was added
2-(4-bromophenyl)-2-oxoethyl 4-(heptyloxy)benzoate (1.0 g, 2.3
mmol) and acetamide (4.91 g, 83.0 mmol) in DCM (10 mL). The
reaction mixture was heated to 50.degree. C. then 140.degree. C.
for 16 h, DCM was distilled off. The reaction mixture was cooled,
diluted with acetonitrile and stirred at room temperature for 1 h.
The precipitate was isolated by filtration to afford 273 mg (23%)
of 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)oxazole as a brown
solid. LCMS-ESI (m/z) calculated for C.sub.22H.sub.24BrNO.sub.2:
413.1; found 414.0 [M+H].sup.+, t.sub.R=3.00 min. (Method 4).
(S)-methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)oxa-
zol-4-yl)phenyl)propanoate
##STR00151##
To zinc (104 mg, 1.59 mmol) stirring in DMF (1.5 mL) was added
iodine (20.2 mg, 0.08 mmol). After the color disappeared,
(R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (175 mg,
0.53 mmol) and further iodine (20.2 mg, 0.08 mmol) were added.
After 30 min, the mixture was de-gassed by bubbling through N.sub.2
then treated with 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)oxazole
(220 mg, 0.53 mmol), Pd.sub.2dba.sub.3 (12.2 mg, 0.01 mmol) and
dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (10.9
mg, 0.03 mmol) followed by THF (1 mL). The reaction mixture was
heated to 50.degree. C. for 2 h, cooled to room temperature and
purified by column chromatography (gradient of 15-95% EA in
iso-hexanes) to afford 188 mg (65%) of (S)-methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)oxazol-4-yl)p-
henyl)propanoate. LCMS-ESI (m/z) calculated for
C.sub.31H.sub.40N.sub.2O.sub.6: 536.6; found 537.0 [M+H].sup.+,
t.sub.R=3.72 min. (Method 11).
Compound 78 was prepared from (S)-methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)oxazol-4-yl)p-
henyl)propanoate and 4-(tert-butyl)benzoic acid using General
Procedures 8, 7 then 4.
2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole
##STR00152##
To a stirring solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone
(INT-4) (1.37 g, 4.38 mmol) in EtOH (10 mL) were added
4-bromobenzothioamide (0.95 g, 4.38 mmol) and isopropanol (10 mL).
The reaction mixture was stirred at room temperature for 16 h. The
solid was isolated by filtration, washed with EtOH (5 mL) then
taken up in DCM (10 mL) and NaHCO.sub.3 (20 mL) and stirred for 1 h
at room temperature. The solid was isolated by filtration, washed
with water (2.times.10 mL) and acetonitrile (2.times.4 mL) then
dried to afford 1.02 g (52%) of
2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole as a white
micro-crystalline solid. LCMS-ESI (m/z) calculated for
C.sub.22H.sub.24BrNO.sub.S: 429.1; found 430.0 [M+H].sup.+,
t.sub.R=3.20 min. (Method 4).
(S)-methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)thi-
azol-2-yl)phenyl)propanoate
##STR00153##
To a stirring suspension of zinc (228 mg, 3.49 mmol) in DMF (2 mL)
was added diiodine (44 mg, 0.17 mmol). When the color was
discharged, (R)-methyl
2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (382 mg, 1.16 mmol)
and further diiodine (44.2 mg, 0.17 mmol) were added. After
stirring at room temperature for 30 min, the reaction mixture was
de-gassed by bubbling through N.sub.2 then
2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole (500 mg, 1.16
mmol), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine
(23.8 mg, 0.06 mmol), Pd.sub.2dba.sub.3 (26 mg, 0.03 mmol) and DMF
(2 mL) were added. The reaction mixture was heated to 50.degree. C.
for 3 h, cooled and purified by column chromatography (10-80% EA in
iso-hexanes) to afford 620 mg (96%) of (S)-methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)thiazol-2-yl)-
phenylpropanoate. LCMS-ESI (m/z) calculated for
C.sub.31H.sub.40N.sub.2O.sub.5S: 552.3; no ion observed,
t.sub.R=3.37 min. (Method 4).
Compound 79 was prepared from (S)-methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)thiazol-2-yl)-
phenylpropanoate and 4-(tert-butyl)benzoic acid using General
Procedures 8, 7 then 4.
4-(heptyloxy)benzothioamide
##STR00154##
To stirring suspension of 4-(heptyloxy)benzamide (1.24 g, 5.29
mmol) in DME (20 mL) and THF (10 mL) was added
2,4-bis(4-phenoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide
(2.80 g, 5.29 mmol). The reaction mixture was stirred at room
temperature for 16 h. The reaction mixture was concentrated onto
silica and purified by column chromatography (0-60% EA in
iso-hexanes) to afford 1.4 g (62%) of 4-(heptyloxy)benzothioamide
as a yellow waxy solid. LCMS-ESI (m/z) calculated for
C.sub.14H.sub.21NOS: 251.4; found 252.0 [M+H].sup.+, t.sub.R=3.13
min. (Method 6).
4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole
##STR00155##
To a stirring mixture of 4-(heptyloxy)benzothioamide (1.30 g, 5.17
mmol) in isopropanol (20 mL) was added
2-bromo-1-(4-bromophenyl)ethanone (1.44 g, 5.17 mmol). The
precipitate was collected by filtration and washed with EtOH
(2.times.5 mL). The filter cake was slurried with NaHCO.sub.3
(2.times.20 mL), water (2.times.20 mL) then EtOH (2.times.5 mL) and
dried to afford 926 mg (41%) of
4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole as a pale yellow
powder. LCMS-ESI (m/z) calculated for C.sub.22H.sub.24BrNOS: 429.1;
found 430.0 [M+H].sup.+, t.sub.R=3.41 min. (Method 4).
(S)-methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)thi-
azol-4-yl)phenyl)propanoate
##STR00156##
To a stirring mixture of zinc (182 mg, 2.79 mmol) in DMF (2 mL) was
added diiodine (35.4 mg, 0.14 mmol). When the color was discharged,
further diiodine (35.4 mg, 0.14 mmol) and (R)-methyl
2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (306 mg, 0.93 mmol)
were added. After 30 min, DMF (1 mL) was added and the mixture
de-gassed by bubbling through N.sub.2. To the reaction mixture were
added 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)thiazole (400 mg,
0.93 mmol), Pd.sub.2dba.sub.3 (21 mg, 0.02 mmol) and
dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (19 mg,
0.05 mmol), the mixture was further de-gassed then heated to
50.degree. C. for 3 h. The reaction mixture was cooled and purified
by column chromatography (10-80% EA in iso-hexanes). The product
obtained was taken into DCM (4 mL) and washed with water (20 mL)
and dried through a hydrophobic frit. The organics were suspended
in ACN (4 mL) and concentrated to afford 432 mg (83%) of (S)-methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)thiazol-4-yl)-
phenyl)propanoate as a yellow foam. LCMS-ESI (m/z) calculated for
C.sub.31H.sub.40N.sub.2O.sub.5S: 552.7; no ion observed,
t.sub.R=3.36 min. (Method 4).
Compound 80 was prepared from (S)-methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)thiazol-4-yl)-
phenyl)propanoate and 4-(tert-butyl)benzoic acid using General
Procedures 8, 7 then 4.
4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)benzaldehyde
##STR00157##
To a stirring suspension of 4-(thiazol-2-yl)benzaldehyde (349 mg,
1.84 mmol), tricyclohexylphosphine (27 mg, 0.07 mmol), pivalic acid
(64.2 .mu.l, 0.55 mmol), potassium carbonate (382 mg, 2.77 mmol)
and palladium (II) acetate (8 mg, 0.04 mmol) in DMA (5.15 mL) under
nitrogen was added a solution of 1-bromo-4-(heptyloxy)benzene (500
mg, 1.84 mmol) in DMA (1 mL). The reaction mixture was evacuated
and purged with nitrogen 3 times then heated at 100.degree. C. for
6 h. Once cooled, the reaction mixture was diluted with EA (40 mL),
washed with water (3.times.40 mL) and brine (40 mL). The organic
phase was dried over MgSO.sub.4, filtered and concentrated in vacuo
to afford a brown-green solid. The crude product was purified by
chromatography (0-50% EA in hexanes) to afford 270 mg (37%) of
4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)benzaldehyde as an
iridescent yellow solid. LCMS-ESI (m/z) calculated for
C.sub.23H.sub.25NO.sub.2S: 379.5; found 380.0 [M+H].sup.+,
t.sub.R=2.99 min. (Method 8).
methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-
-2-yl)phenyl) acrylate
##STR00158##
A stirring mixture of 1,1,3,3-tetramethylguanidine (86 .mu.l, 0.69
mmol) was added to a suspension of
4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)benzaldehyde (260 mg, 0.685
mmol) and methyl
2-((tert-butoxycarbonyl)amino)-2-(dimethoxyphosphoryl)acetate (185
mg, 0.62 mmol) in anhydrous THF (10 mL) under nitrogen, at
-70.degree. C. The reaction mixture was stirred at -70.degree. C.
for 1 h then at room temperature for 18 h. The reaction mixture was
diluted with DCM (50 mL), washed with water (50 mL), passed through
a phase separation cartridge and the organic phase concentrated in
vacuo to afford a yellow solid. The solid was triturated with
EA/EtOH (20 mL) and the collected solid washed with EtOH (10 mL)
and Et.sub.2O to afford 284 mg (79%) of methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazo-
l-2-yl)phenyl) acrylate as a yellow solid. LCMS-ESI (m/z)
calculated for C.sub.31H.sub.38N.sub.2O.sub.5S: 550.7; found 551.0
[M+H].sup.+, t.sub.R=3.11 min. (Method 8).
methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-
-2-yl)phenyl)propanoate
##STR00159##
A stirring mixture of methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)-
phenyl)acrylate (50 mg, 0.091 mmol) dissolved in dioxane (5 mL) was
hydrogenated using an H-Cube hydrogenator (10% Pd/C, 30.times.4 mm,
full hydrogen, 40.degree. C., 1 mL/min). The reaction mixture was
concentrated in vacuo to afford 21 mg (29%) of methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)-
phenyl)propanoate as a yellow solid. LCMS-ESI (m/z) calculated for
C.sub.31H.sub.40N.sub.2O.sub.5S: 552.7; found 553.0 [M+H].sup.+,
t.sub.R=1.85 min. (Method 8).
Compound 81 was prepared from methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)-
phenyl)propanoate and 4-(tert-butyl)benzoyl chloride using General
Procedures 8, 3 then 4.
Compound 82 was prepared in a similar fashion to
2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phe-
nyl)propanoic acid (Compound 81) using
4-(2-(4-(heptyloxy)phenyl)thiazol-5-yl)benzaldehyde in place of
4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)benzaldehyde.
(S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-
-thiadiazol-2-yl)phenyl)propanoate
##STR00160##
Prepared using INT-3: To a stirring solution of
2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide
(65.7 mg, 0.16 mmol) in THF (3 mL) was added (S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(2-(4-(heptyloxy)benzoyl)hydrazinecarbon-
yl)phenyl)propanoate (INT-3) (100.0 mg, 0.16 mmol) and the mixture
heated to 65.degree. C. After 1 h, the reaction mixture was
concentrated and purified by column chromatography (10-100% EA in
iso-hexanes) to afford 37.0 mg (29%) of (S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-thiadiazo-
l-2-yl)phenyl)propanoate as a yellow solid. LCMS-ESI (m/z)
calculated for C.sub.36H.sub.43N.sub.3O.sub.4S: 613.8; no ion
observed, t.sub.R=3.31 min. (Method 4).
Compound 83 was prepared from (S)-methyl 2-(4-(tert-butyl)
benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-thiadiazol-2-yl)phenyl)pro-
panoate using General Procedure 4.
Compound 84 was prepared using 3-bromo-5-chloro-1,2,4-thiadiazole,
(4-(heptyloxy)phenyl)boronic acid and tert-butyl (S)-methyl
2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl)propanoate (INT-13) using General Procedures 10, 10,
and 8 sequentially.
(S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)-oxy)-phe-
nyl)propanoate (INT-5)
##STR00161##
Prepared using General Procedure 9: A stirred solution of
(S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate
hydrate (25 g, 64.2 mmol) in DCM (100 mL) was treated with
MgSO.sub.4 (4.01 g, 33.7 mmol). After 15 min, the mixture was
filtered and washed with DCM (2.times.20 mL). The organics were
treated with N-ethyl-N-isopropylpropan-2-amine (17.41 g, 134.7
mmol) and stirred. This solution was treated with
1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide
(26.44 g, 74.01 mmol) and the mixture was allowed to stir overnight
at room temperature. The mixture was treated with water (50 mL) and
saturated aqueous NaHCO.sub.3 (20 mL) and stirred vigorously for 10
min. The layers were separated and the organic layer was further
washed with saturated aqueous NaHCO.sub.3 (2.times.50 mL), water
(50 mL), and saturated aqueous NaHCO.sub.3 (50 mL) and
concentrated. The compound was purified by chromatography
(EA/hexanes) to afford 26.85 g (79%) of (S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)pheny-
l)propanoate (INT-5). LCMS-ESI (m/z) calculated for
C.sub.22H.sub.24F.sub.3NO.sub.7S: 503.1; found 526.1 [M+Na].sup.+,
t.sub.R=4.12 min (Method 3).
(S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)propanoate (INT-6)
##STR00162##
A solution of (S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)pheny-
l)propanoate (INT-5) (26.85 g, 53.4 mmol), potassium acetate (15.71
g, 160.1 mmol), bis-pinacolatoborane (27.1 g, 106.7 mmol) and DMSO
(100 mL) was degassed with a steady flow of nitrogen gas for 5
minutes. To this solution was added PdCl.sub.2(dppf) (1.95 g, 2.67
mmol) and the solution further degassed and kept under an
atmosphere of nitrogen. The mixture was heated at 100.degree. C.
for 18 h then cooled to room temperature and diluted with EA (50
mL) and washed with saturated aqueous NaHCO.sub.3 (20 mL), water
(3.times.30 mL), dried over MgSO.sub.4, filtered, and the solvent
removed under reduced pressure. The compound was purified by column
chromatography to give 11.10 g (41%) of (S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)propanoate (INT-6) as an oil. LCMS-ESI (m/z)
calculated for C.sub.27H.sub.36BNO.sub.6: 481.3; found 504.3
[M+Na].sup.+, t.sub.R=4.21 min (Method 3). .sup.1H NMR (400 MHz,
DMSO) .delta. 7.72 (d, J=8.3 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H),
7.42-7.11 (m, 6H), 4.98 (s, 2H), 4.22-4.08 (m, 1H), 3.03 (dd,
J=13.7, 5.2 Hz, 1H), 2.85 (dd, J=13.6, 10.1 Hz, 1H), 1.36 (s, 6H),
1.30 (s, 9H), 1.22-1.13 (m, 6H).
(S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)-phenyl)propan-
oate (INT-7)
##STR00163##
Prepared using General Procedure 10: A stirred mixture of
(S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)propanoate (INT-6) (21.7 g, 45.0 mmol) and
5-bromo-2-iodopyrimidine (15.4 g, 54.0 mmol) in dioxane (400 mL)
with sodium carbonate decahydrate (25.7 g, 90 mmol) in water (100
mL) was de-gassed. PdCl.sub.2(dppf) (0.99 g, 1.4 mmol) was added
and the mixture further de-gassed then heated to reflux for 5 h.
The mixture was allowed to cool while stirring overnight. The
mixture was poured onto water (1 L) and EA (300 mL) and stirred for
30 min. The mixture was filtered and the layers were separated. The
aqueous layer was further extracted with EA (2.times.200 mL) and
the combined organic layers were washed with water (2.times.100 mL)
then brine (50 mL), dried over MgSO.sub.4 and concentrated. Column
chromatography (EA/hexanes) gave 14.84 g (63%) of (S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propano-
ate (INT-7). LCMS-ESI (m/z) calculated for
C.sub.25H.sub.26BrN.sub.3O.sub.4: 511.1; found 534.0 [M+Na].sup.+,
t.sub.R=2.97 min (Method 11).
(S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)-pyrimidin-2--
yl)phenyl)propanoate (INT-8)
##STR00164##
Prepared using General Procedure 10: A stirred solution of
(S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propano-
ate (INT-7) (759 mg, 1.48 mmol), (4-(heptyloxy)phenyl)boronic acid
(455 mg, 1.93 mmol) and sodium bicarbonate (311 mg, 3.70 mmol) in
acetonitrile (5 ml), THF (5 ml), and water (4 ml) was degassed with
N.sub.2 for 5 min. Pd(dppf)Cl.sub.2 (108 mg, 0.15 mmol) was added
and the reaction was heated to 110.degree. C. in the microwave for
50 min. The reaction was diluted with EA and water then filtered.
The organic phase was dried over MgSO4, filtered, and concentrated.
The crude product was purified by chromatography on silica gel
(EA/hexanes) to afford 591 mg (62%) of (S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-y-
l)phenyl)propanoate (INT-8) as a yellow solid. LCMS-ESI (m/z)
calculated for C.sub.38H.sub.45N.sub.3O.sub.5: 623.8; no m/z
observed, t.sub.R=3.42 min (Method 8).
(S)-tert-butyl
2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate
(INT-9)
##STR00165##
To a stirred solution of (S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-y-
l)phenyl)propanoate (INT-8) (591 mg, 0.95 mmol) in EA (25 ml) was
added Pd/C (101 mg, 0.09 mmol) and the suspension degassed with
H.sub.2. The mixture was stirred vigorously under an atmosphere of
H.sub.2 overnight then filtered through celite and the filtrate was
concentrated to give 405 mg (83%) of (S)-tert-butyl
2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate
(INT-9). LCMS-ESI (m/z) calculated for
C.sub.30H.sub.39N.sub.3O.sub.3: 489.3; found: 490.2 [M+H].sup.+,
t.sub.R=2.35 min (Method 8).
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-y-
l)-phenyl)propanoic acid (Compound 85)
##STR00166##
A stirred solution of (S)-tert-butyl
2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate
(INT-9) (1.34 g, 2.74 mmol) and 4-(tert-butyl)benzoic acid (0.54 g,
3.01 mmol) in DMF (5 mL) and N-ethyl-N-isopropylpropan-2-amine
(1.01 ml, 5.47 mmol) was treated with HATU (1.09 g, 2.87 mmol).
After stirring for 1 h, the mixture was treated with water (60 mL)
and iso-hexanes (20 mL) and stirred for 1 h. The product was
collected by filtration, washed with water (3.times.10 mL) then
iso-hexanes (10 mL) and dried in the vacuum oven. The ester was
taken up in DCM (5 mL) and treated with TFA (5 mL). After 2 h, the
mixture was treated with toluene (5 mL) and evaporated. The residue
was taken up in DMSO (6 mL) then treated with water (20 mL) and
stirred for 1 h. The product was collected by filtration, washed
with water (3.times.15 mL) then acetonitrile (2.times.5 mL), and
dried in the vacuum oven to give 1.40 g (85%) of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) as a white solid. LCMS-ESI
(m/z) calculated for C.sub.37H.sub.43N.sub.3O.sub.4; 593.3; found:
594.0 [M+H].sup.+, t.sub.R=11.18 min (Method 9) and 97% e.e.
(Chiral Method). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 12.79 (br,
s, 1H), 9.16 (s, 2H), 8.66 (d, J=8.2 Hz, 1H), 8.45-8.27 (m, 2H),
7.89-7.69 (m, 4H), 7.57-7.38 (m, 4H), 7.18-7.02 (m, 2H), 4.77-4.62
(m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.30-3.24 (m, 1H), 3.22-3.12 (m,
1H), 1.80-1.68 (m, 2H), 1.48-1.20 (m, 17H), 0.96-0.82 (m, 3H).
Compounds 86-102, 104-158 and 296 were prepared from (S)-tert-butyl
2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate
(INT-8) using General Procedures 3 or 7 followed by 4 or 8.
(S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(tert-butyl)phenyl)-pyrimidin-2-
-yl)phenyl)propanoate (INT-10)
##STR00167##
Prepared using General Procedure 10: A stirred solution of
(S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propano-
ate (INT-7) (0.96 g, 1.86 mmol), (4-(tert-butyl)phenyl)boronic acid
(0.43 g, 2.42 mmol) and sodium bicarbonate (0.39 g, 4.66 mmol) in
acetonitrile (5 ml), THF (5 ml) and water (5 ml) was degassed with
N.sub.2 for 5 min. Pd(dppf)Cl.sub.2 (0.136 g, 0.186 mmol) was added
and the reaction was heated to 110.degree. C. in the microwave for
45 min. The reaction was diluted with EA (50 mL) and filtered over
celite. The organic phase was washed with water (100 mL) and
concentrated. The crude product was purified by chromatography on
silica gel (EA/isohexanes) to afford 757 mg (70%) of (S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2--
yl)phenyl)propanoate (INT-10) as a white powder. LCMS-ESI (m/z)
calculated for C.sub.35H.sub.39N.sub.3O.sub.4: 565.3; no m/z
observed, t.sub.R=3.39 min (Method 8).
(S)-tert-butyl
2-amino-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)-propanoate
(INT-11)
##STR00168##
To a stirred solution of (S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2--
yl)phenyl)propanoate (INT-10) (757 mg, 1.34 mmol) in EA (100 ml)
was added Pd/C (142 mg, 0.13 mmol) and the suspension degassed with
H.sub.2. The mixture was stirred vigorously under an atmosphere of
H.sub.2 overnight then filtered through celite and the filtrate was
concentrated to give 532 mg (88%) of (S)-tert-butyl
2-amino-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)propanoate
(INT-11). LCMS-ESI (m/z) calculated for
C.sub.27H.sub.33N.sub.3O.sub.2: 431.3; found: 432.0 [M+H].sup.+,
t.sub.R=2.01 min (Method 4).
Compounds 159-181 were prepared from (S)-tert-butyl
2-amino-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)propanoate
(INT-11) using General Procedures 3 or 7 followed by 4 or 8.
Compound 182 was prepared in a manner analogous to
(S)-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)-2-(5-(tert-butyl-
)thiophene-2-carboxamido)propanoic acid (Compound 165) starting
from (R)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate.
Compound 183 was prepared from
(S)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)-2-(4-hydroxybenzamido)pr-
opanoic acid (Compound 114) using General Procedure 13.
Compounds 184-190 were prepared from (S)-tert-butyl
2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate
(INT-9) using General Procedures 3 and 8 sequentially.
Compound 191 was prepared in a manner analogous to
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) starting from (R)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate.
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl-
)-pyrimidin-2-yl)phenyl)propanoic acid (Compound 192)
##STR00169##
A stirring solution of (S)-tert-butyl
2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate
(INT-9) (5.50 g, 11.23 mmol) and
5-(tert-butyl)thiophene-2-carboxylic acid (2.13 g, 11.57 mmol) in
DMF (50 mL) and DIEA (6.22 ml, 33.70 mmol) was treated portion wise
with HATU (4.48 g, 11.79 mmol). After stirring for 1 h, the mixture
was treated with water (200 mL) and iso-hexanes (20 mL) and stirred
for 10 min. The product was collected by filtration, washed with
iso-hexanes (2.times.30 mL), water (2.times.50 mL) then MeOH (20
mL) and iso-hexanes (30 mL). The ester was taken up in DCM (50 mL)
and treated with TFA (10 mL). After 1 h, additional TFA (15 mL) was
added. After a further 5 h, the mixture was treated with toluene
(20 mL) and concentrated. The residue was washed with acetonitrile
(25 mL) then taken up in DMSO (20 mL) then treated with water (100
mL) and stirred for 1 h. The product was collected by filtration,
washed with water (4.times.50 mL) then acetonitrile (3.times.30
mL), and dried in a vacuum oven to give 5.30 g (75%) of
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) as an
off-white solid. LCMS-ESI (m/z) calculated for
C.sub.35H.sub.41N.sub.3O.sub.4S: 599.3; no m/z observed,
t.sub.R=11.10 min (Method 10). The chiral purity was 98% e.e.
(Chiral Method). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 12.87 (s,
1H), 9.17 (s, 2H), 8.68 (d, J=8.3 Hz, 1H), 8.47-8.17 (m, 2H),
7.96-7.71 (m, 2H), 7.64 (d, J=3.8 Hz, 1H), 7.55-7.29 (m, 2H),
7.26-7.02 (m, 2H), 6.93 (d, J=3.8 Hz, 1H), 4.79-4.48 (m, 1H), 4.03
(t, J=6.5 Hz, 2H), 3.27 (dd, J=13.9, 4.5 Hz, 1H), 3.12 (dd, J=13.9,
10.6 Hz, 1H), 1.90-1.58 (m, 2H), 1.58-1.01 (m, 17H), 1.01-0.69 (m,
3H).
Compound 193 was prepared in a manner analogous to
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) starting from
(R)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate.
tert-butyl (4-(tert-butyl)benzoyl)-L-tyrosinate
##STR00170##
Prepared using General Procedure 7. Into a solution of
4-(tert-butyl)benzoic acid (8.3 g, 46.4 mmol) in DMF (100 mL) were
added HATU (19.2 g, 50.6 mmol), TEA (17.6 mL, 126.4 mmol) and
(S)-tert-butyl 2-amino-3-(4-hydroxyphenyl)propanoate (10.0 g, 42.1
mmol). After 5 h, the reaction mixture was diluted with EA, washed
with saturated aqueous NaHCO.sub.3 and brine, then dried
(Na.sub.2SO.sub.4), concentrated, and purified by chromatography
(EA/hexanes) to provide 12.9 g (69%) of tert-butyl
(4-(tert-butyl)benzoyl)-L-tyrosinate. LCMS-ESI (m/z) calculated for
C.sub.24H.sub.31NO.sub.4: 397.5; no m/z observed, t.sub.R=3.59 min
(Method 1). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.71-7.65 (m,
2H), 7.47-7.39 (m, 2H), 7.04 (t, J=5.7 Hz, 2H), 6.78-6.70 (m, 2H),
6.59 (d, J=7.5 Hz, 1H), 4.91 (dt, J=7.5, 5.6 Hz, 1H), 3.15 (qd,
J=14.0, 5.6 Hz, 2H), 1.45 (s, 9H), 1.33 (s, 9H).
tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfony-
l)oxy)phenylpropanoate (INT-12)
##STR00171##
Prepared using General Procedure 9. Into a solution of tert-butyl
(4-(tert-butyl)benzoyl)-L-tyrosinate (8.0 g, 17.9 mmol) were added
DIEA (3.7 mL, 1.2 mmol) and N-Phenyl
bis(trifluoromethanesulfonimide) (7.0 g, 19.7 mmol). After stirring
for 36 h, the reaction mixture was diluted with DCM then washed
with 10% aqueous citric acid and saturated aqueous NaHCO.sub.3. The
organic layer was dried over Na.sub.2SO.sub.4, and concentrated to
provide 9.5 g (100%) tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phen-
yl)propanoate (INT-12), which was used without further
purification. LCMS-ESI (m/z) calculated for
C.sub.25H.sub.30F.sub.3NO.sub.6S: 529.6; no m/z observed,
t.sub.R=4.42 min (Method 1). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.71-7.65 (m, 2H), 7.49-7.43 (m, 2H), 7.32-7.26 (m, 2H),
7.22-7.16 (m, 2H), 6.69 (d, J=7.0 Hz, 1H), 4.94 (dt, J=6.9, 5.9 Hz,
1H), 3.24 (t, J=7.1 Hz, 2H), 1.41 (s, 9H), 1.33 (s, 9H).
tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-
-dioxaborolan-2-yl)phenyl)propanoate (INT-13)
##STR00172##
Into a degassed solution of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phen-
yl)propanoate (INT-12) (9.5 g, 24 mmol), KOAc (7.0 g, 72 mmol), and
bis-pinacolatoborane (9.1 g, 36 mmol) in DMSO (20 mL) was added
Pd(dppf)Cl.sub.2 (0.87 g, 1 mmol). The reaction mixture was heated
at 100.degree. C. for 12 h under an atmosphere of N.sub.2. The
reaction mixture was diluted with EA then washed with saturated
aqueous NaHCO.sub.3 and H.sub.2O. The organic layer was dried over
Na.sub.2SO.sub.4, concentrated, and purified by chromatography
(EA/hexanes) to provide 7.2 g (60%) of tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13). LCMS-ESI (m/z) calculated for
C.sub.30H.sub.42BNO.sub.5: 507.5; no m/z observed, t.sub.R=4.53 min
(Method 1). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.74 (d,
J=8.0 Hz, 2H), 7.72-7.67 (m, 2H), 7.48-7.43 (m, 2H), 7.21 (d, J=8.0
Hz, 2H), 6.59 (d, J=7.4 Hz, 1H), 5.05-4.92 (m, 1H), 3.27 (qd,
J=13.7, 5.4 Hz, 2H), 1.47 (s, 9H), 1.36 (m, 21H).
tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzam-
ido)propanoate (INT-14)
##STR00173##
Prepared using General Procedure 10. Into a degassed solution of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13) (1.0 g, 2.0 mmol), NaHCO.sub.3
(420 mg, 3.9 mmol), and 5-bromo-2-iodopyrimidine (615 mg, 2.2 mmol)
in 2/2/1 ACN/THF/H.sub.2O was added Pd(dppf)Cl.sub.2 (140 mg, 0.2
mmol). The reaction mixture was heated at 110.degree. C. for 1 h in
a microwave reactor. The reaction mixture was concentrated,
dissolved in DCM and washed with H.sub.2O. The organic layer was
dried over Na.sub.2SO.sub.4, concentrated, and purified by
chromatography EA/hexanes) to provide 630 mg (58%) of tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propan-
oate (INT-14). LCMS-ESI (m/z) calculated for
C.sub.28H.sub.32BrN.sub.4O.sub.3: 538.5; no m/z observed,
t.sub.R=4.66 min (Method 1). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.84-8.78 (s, 2H), 8.31 (t, J=7.0 Hz, 2H), 7.75-7.64 (m,
2H), 7.46-7.38 (m, 2H), 7.30 (dd, J=12.9, 7.1 Hz, 2H), 6.65 (d,
J=7.2 Hz, 1H), 5.10-4.94 (m, 1H), 3.43-3.20 (m, 2H), 1.45 (s, 9H),
1.32 (s, 9H).
Compounds 194-236 were prepared from tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propan-
oate (INT-14) using General Procedures 10 and 8 sequentially.
tert-butyl (5-(tert-butyl)thiophene-2-carbonyl)-L-tyrosinate
##STR00174##
Prepared using General Procedure 7. Into a solution of
5-(tert-butyl)thiophene-2-carboxylic acid (1.93 g, 10.0 mmol) in
DMF (20 mL) were added HATU (4.56 g, 12.0 mmol) and TEA (4.18 mL,
30.0 mmol). The mixture was stirred at room temperature for 30 min
and (S)-tert-butyl 2-amino-3-(4-hydroxyphenyl)propanoate (2.37 g,
10.0 mmol) was added. After 1 h, the reaction mixture was poured
into 400 mL of ice-water and the solid was filtered. The solid was
dissolved in DCM and EA, dried over MgSO.sub.4, concentrated, and
purified by chromatography (EA/hexanes) to provide 3.6 g (89%) of
tert-butyl (5-(tert-butyl)thiophene-2-carbonyl)-L-tyrosinate.
LCMS-ESI (m/z) calculated for C.sub.22H.sub.29NO.sub.4S: 403.2;
found: 426.1 [M+Na].sup.+, t.sub.R=9.07 min (Method 2).
tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(((trifluoro-
methyl)sulfonyl)oxy)phenyl)propanoate (INT-15)
##STR00175##
Prepared using General Procedure 9. Into a solution of tert-butyl
(5-(tert-butyl)thiophene-2-carbonyl)-L-tyrosinate (3.52 g, 8.72
mmol) were added DIEA (4.56 mL, 26.17 mmol) and N-phenyl
bis(trifluoromethanesulfonimide) (3.27 g, 9.16 mmol). After
stirring for 18 h, the reaction mixture was diluted with DCM then
washed with saturated aqueous NaHCO.sub.3. The organic layer was
dried over MgSO.sub.4 and concentrated. The crude product was
purified by chromatography to provide 4.10 g (87.6%) of tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(((trifluoromethyl)sul-
fonyl)oxy)phenyl)propanoate (INT-15). LCMS-ESI (m/z) calculated for
C.sub.23H.sub.28F.sub.3NO.sub.6S.sub.2: 535.1; no m/z observed,
t.sub.R=4.22 min (Method 3).
tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tet-
ramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (INT-16)
##STR00176##
Into a degassed solution of tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(((trifluoromethyl)sul-
fonyl)oxy)phenyl)propanoate (INT-15) (3.89 g, 7.26 mmol), KOAc
(2.14 g, 21.79 mmol), and bis-pinacolatoborane (2.40 g, 9.44 mmol)
in DMSO (50 mL) was added Pd(dppf)Cl.sub.2 (0.27 g, 0.36 mmol). The
reaction mixture was heated at 100.degree. C. for 18 h under an
atmosphere of N.sub.2. The reaction mixture was poured into 600 mL
of ice-water and the solid was filtered. The precipitate was
diluted with EA, dried over MgSO.sub.4, concentrated, and purified
by chromatography (EA/hexanes) to provide 3.68 g (99%) of
tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1-
,3,2-dioxaborolan-2-yl)phenyl)propanoate (INT-16). LCMS-ESI (m/z)
calculated for C.sub.28H.sub.4013 NO.sub.5S: 513.3; no m/z
observed, t.sub.R=4.51 min (Method 3).
tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thioph-
ene-2-carboxamido)propanoate (INT-17)
##STR00177##
Prepared using General Procedure 10. Into a degassed solution of
tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1-
,3,2-dioxaborolan-2-yl)phenyl)propanoate (INT-16) (510 mg, 1.0
mmol) and 5-bromo-2-iodopyrimidine (570 mg, 2.0 mmol) in 2/2/1
ACN/THF/saturated aqueous NaHCO.sub.3 (10 mL) was added
Pd(dppf)Cl.sub.2 (30 mg, 0.4 mmol). The reaction mixture was heated
at 120.degree. C. for 1 h in a microwave reactor. The reaction
mixture was diluted with water (100 mL) and EA (50 mL) and filtered
over Celite. The aqueous layer was extracted with EA (3.times.30
mL) and the combined organic layer was dried over MgSO.sub.4,
concentrated, and purified by chromatography (EA/hexanes) to
provide 342 mg (63%) of tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoate (INT-17). LCMS-ESI (m/z) calculated for
C.sub.26H.sub.30BrN.sub.3O.sub.3: 543.1; found: 488.0
[M-tBu+H].sup.+, t.sub.R=10.95 min (Method 2).
Compounds 237-247 were prepared from tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoate (INT-17) using General Procedures 10 and 8
sequentially.
tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-cyanopyrimidin-2-yl)phe-
nyl)-propanoate (INT-18)
##STR00178##
Prepared using General Procedure 1. Into a degassed solution of
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propan-
oate (INT-14) (100 mg, 0.190 mmol), and Zn(CN).sub.2 (44 mg, 0.370
mmol) in NMP (5 mL) was added Pd(PPh.sub.3).sub.4 (2 mg, 0.002
mmol). The mixture was heated for 45 min at 80.degree. C. in a
microwave reactor then partitioned between DCM and H.sub.2O. The
organic layer was dried over Na.sub.2SO.sub.4, concentrated, and
purified by chromatography (EA/hexanes) to provide 75 mg (84%) of
tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-cyanopyrimidin-2-yl)phenyl)propan-
oate (INT-18). LCMS-ESI (m/z) calculated for
C.sub.29H.sub.32N.sub.4O.sub.3: 484.60; no m/z observed,
t.sub.R=4.17 min (Method 1). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.97 (s, 2H), 8.38 (d, J=7.9 Hz, 2H), 7.67 (d, J=8.0 Hz,
2H), 7.46-7.35 (m, 2H), 7.33 (d, J=7.9 Hz, 2H), 6.77 (d, J=6.8 Hz,
1H), 4.96 (d, J=6.1 Hz, 1H), 3.27 (dd, J=13.1, 8.0 Hz, 2H), 1.37
(d, J=34.5 Hz, 9H), 1.26 (d, J=21.0 Hz, 9H).
tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(N-hydroxycarbamimidoyl-
)-pyrimidin-2-yl)phenyl)propanoate
##STR00179##
Prepared using General Procedure 2. A solution of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-cyanopyrimidin-2-yl)phenyl)propan-
oate (INT-18) (35 mg, 0.07 mmol), hydroxylamine (25 .mu.L, 0.36
mmol, 50% solution in H.sub.2O), and NEt.sub.3 (11 .mu.L, 0.08
mmol) in EtOH (5 mL) was heated at 80.degree. C. for 1.5 h. The
reaction mixture was concentrated, dissolved in DCM and washed with
H.sub.2O to provide 22 mg of tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(N-hydroxycarbamimidoyl)pyrimidin-
-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for
C.sub.29H.sub.35N.sub.5O.sub.4: 517.6; found 462.2 [M-tBu+H].sup.+,
t.sub.R=3.72 min (Method 1). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.19 (s, 2H), 8.42 (d, J=8.2 Hz, 2H), 7.67 (dd, J=8.5, 2.1
Hz, 2H), 7.40 (dd, J=9.2, 8.0 Hz, 2H), 7.34 (dd, J=10.3, 8.4 Hz,
2H), 6.74 (dd, J=7.1, 4.7 Hz, 1H), 5.00 (q, J=5.6 Hz, 1H), 2.83 (d,
J=5.3 Hz, 2H), 1.44 (s, 9H), 1.28 (d, J=22.0 Hz, 9H).
tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,2,4-oxadiazo-
l-3-yl)pyrimidin-2-yl)phenyl)propanoate (Compound 248)
##STR00180##
Prepared using General Procedure 5. A solution of heptanoic acid (7
mg, 0.05 mmol), HOBt (12 mg, 0.09 mmol) and EDC (13 mg, 0.09 mmol)
was heated at 80.degree. C. for 2 h. The reaction mixture was
diluted with EtOAc and washed with NaHCO.sub.3. The organic layer
was dried over Na.sub.2SO.sub.4 and concentrated. The resulting
mixture was dissolved in EtOH (2 mL) and heated for 45 min at
80.degree. C. in a microwave reactor. The mixture was concentrated
and purified by preparatory HPLC to provide 1.5 mg of tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,2,4-oxadiazol-3-yl)pyr-
imidin-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for
C.sub.36H.sub.45N.sub.5O.sub.4: 611.8; no m/z observed, t.sub.R=5.5
min (Method 1). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.45 (s,
2H), 8.44 (d, J=8.3 Hz, 2H), 7.71 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.5
Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 6.80 (d, J=7.3 Hz, 1H), 5.04 (dd,
J=12.7, 5.5 Hz, 1H), 3.37 (ddd, J=18.9, 13.8, 5.5 Hz, 2H), 3.02 (t,
J=7.6 Hz, 2H), 1.92 (dt, J=15.3, 7.5 Hz, 2H), 1.49 (s, 9H),
1.44-1.28 (m, 15H), 0.93 (t, J=7.1 Hz, 3H).
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,2,4-oxadiazol-3-yl)pyr-
imidin-2-yl)phenyl)propanoate was deprotected using General
Procedure 8 to provide 1.4 mg (6% overall) of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,2,4-oxadiazol-3-yl)pyr-
imidin-2-yl)phenyl)propanoic acid (Compound 248). LCMS-ESI (m/z)
calculated for C.sub.32H.sub.37N.sub.5O.sub.4: 555.68; no m/z
observed, t.sub.R=11.03 min (Method 2). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.41 (s, 2H), 8.47 (d, J=8.2 Hz, 2H), 7.66 (d,
J=8.4 Hz, 2H), 7.42 (dd, J=15.1, 8.4 Hz, 4H), 6.60 (d, J=6.8 Hz,
1H), 5.21-4.95 (m, 1H), 3.43 (ddd, J=20.0, 14.0, 5.6 Hz, 2H),
3.05-2.90 (m, 2H), 1.98-1.76 (m, 2H), 1.55-1.22 (m, 15H), 0.91 (t,
J=7.0 Hz, 3H).
tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydrox-
yphenyl)pyrimidin-2-yl)phenyl)propanoate
##STR00181##
Prepared using General Procedure 10. To a degassed solution of
tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido) propanoate (INT-17) (180 mg, 0.3 mmol), sodium carbonate
(70 mg, 0.7 mmol) and 4-hydroxyphenylboronic acid (55 mg, 0.4 mmol)
in 5 mL of 2/2/1 ACN/THF/H.sub.2O was added Pd(dppf)Cl.sub.2 (24
mg, 0.03 mmol). The reaction mixture was heated at 110.degree. C.
for 45 min in a microwave reactor. The mixture was filtered through
celite, concentrated, then dissolved in DCM and washed with
H.sub.2O. The organic layer was concentrated and purified by prep
HPLC to provide 131 mg (78%) of tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)py-
rimidin-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for
C.sub.32H.sub.35N.sub.3O.sub.4S: 557.7; no m/z observed,
t.sub.R=4.08 min (Method 1). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.98 (s, 2H), 8.35 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.6 Hz,
2H), 7.40-7.31 (m, 3H), 6.94 (d, J=8.5 Hz, 2H), 6.81 (d, J=3.8 Hz,
1H), 6.51 (d, J=7.5 Hz, 1H), 5.00 (dd, J=12.9, 5.8 Hz, 1H), 3.28
(qd, J=13.8, 5.6 Hz, 2H), 1.47 (s, 9H), 1.39 (s, 9.H).
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(decyloxy)phenyl)-
-pyrimidin-2-yl)phenyl)propanoic acid (Compound 249)
##STR00182##
Prepared using General Procedures 12. To a solution of tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(hydroxyphenyl)p-
yrimidin-2-yl)phenyl)propanoate (20 mg, 0.04 mmol) in DMF (0.5 mL)
were added 1-bromodecane (8 .mu.L, 0.05 mmol) and K.sub.2CO.sub.3
(8 mg, 0.05 mmol). The reaction mixture was heated at 40.degree. C.
for 18 h, then diluted with DCM and washed with H.sub.2O. The
organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The
crude material was deprotected using General Procedure 8 then
purified by prepartory HPLC to provide 3.9 mg (17%) of
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(decyloxy)phenyl-
)pyrimidin-2-yl)phenyl)propanoic acid (Compound 249). LCMS-ESI
(m/z) calculated for C.sub.38H.sub.47N.sub.3O.sub.4S: 641.9; no m/z
observed, t.sub.R=13.49 min (Method 2). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.01 (s, 2H), 8.36 (d, J=8.1 Hz, 2H), 7.56 (d,
J=8.7 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H), 7.33 (d, J=3.8 Hz, 1H), 7.03
(d, J=8.8 Hz, 2H), 6.80 (d, J=3.8 Hz, 1H), 6.54 (d, J=6.8 Hz, 1H),
5.13 (d, J=6.8 Hz, 1H), 4.01 (t, J=6.6 Hz, 2H), 3.44 (d, J=4.9 Hz,
2H), 1.91-1.72 (m, 2H), 1.47 (dd, J=15.0, 7.3 Hz, 2H), 1.38 (s,
9H), 1.28 (s, 12H), 0.88 (t, J=6.8 Hz, 3H).
Compounds 250-252 were prepared from tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)py-
rimidin-2-yl)phenyl)propanoate using General Procedure 12 followed
by General Procedure 8.
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(tert-butyl)piperidin-1-yl)pyri-
midin-2-yl)phenyl)propanoic acid (Compound 253)
##STR00183##
Prepared using General Procedure 11. Into a degassed solution of
tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propan-
oate (INT-14) (50 mg, 0.09 mmol), sodium tert-butoxide (18 mg, 0.19
mmol) and 4-tert-butylpiperidine HCl (23 mg, 0.11 mmol) in dioxane
(2.5 mL) were added Pd.sub.2(dba).sub.3 (9 mg, 0.01 mmol) and
2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (6 mg, 0.015
mmol). The reaction mixture was heated for 45 min at 120.degree. C.
in a microwave reactor. The mixture was diluted with EA and washed
with NaHCO.sub.3. The organic layer was dried over
Na.sub.2SO.sub.4, concentrated, and purified by preparatory HPLC.
The isolated intermediate was deprotected using General Procedure 8
to provide 2.9 mg (6%) of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(tert-butyl)piperidin-1-yl)pyr-
imidin-2-yl)phenyl)propanoic acid (Compound 253). LCMS-ESI (m/z)
calculated for C.sub.33H.sub.42N.sub.4O.sub.3: 542.7; found 543.3
[M+H].sup.+, t.sub.R=10.79 min (Purity). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.52 (s, 2H), 8.23 (d, J=8.0 Hz, 2H), 7.72 (d,
J=8.4 Hz, 2H), 7.44 (dd, J=11.3, 8.4 Hz, 4H), 6.79 (d, J=6.8 Hz,
1H), 5.18 (d, J=6.5 Hz, 1H), 3.89 (d, J=11.9 Hz, 2H), 3.47 (d,
J=5.2 Hz, 2H), 2.83 (t, J=11.5 Hz, 2H), 1.88 (d, J=12.0 Hz, 2H),
1.52-1.37 (m, 2H), 1.34 (s, 9H), 1.24 (dd, J=24.7, 12.8 Hz, 1H),
0.92 (s, 9H).
Compound 254 was prepared from tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propan-
oate (INT-14) using General Procedure 11 then General Procedure
8.
tert-butyl
(S)-3-(4-(5-(2H-tetrazol-5-yl)pyrimidin-2-yl)phenyl)-2-(4-(tert-
-butyl)-benzamido)propanoate
##STR00184##
Into a solution of tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-cyanopyrimidin-2-yl)phenyl)propan-
oate (INT-18) (34 mg, 0.07 mmol) in DMF (2 mL) were added
NH.sub.4Cl (7.5 mg, 1.4 mmol) and NaN.sub.3 (7 mg, 0.1 mmol). The
reaction mixture was heated at 100.degree. C. for 3 h then diluted
with EA and washed with NaHCO.sub.3. The organic layer was dried
over Na.sub.2SO.sub.4, concentrated, and purified by preparatory
HPLC to provide 4.6 mg (12%) of tert-butyl
(S)-3-(4-(5-(2H-tetrazol-5-yl)pyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)ben-
zamido)propanoate. LCMS-ESI (m/z) calculated for
C.sub.29H.sub.33N.sub.7O.sub.3: 527.6; no m/z observed,
t.sub.R=3.83 min (Method 1). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.35 (s, 2H), 8.42 (d, J=8.1 Hz, 2H), 7.75 (d, J=8.4 Hz,
2H), 7.47 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H), 7.11 (d, J=7.8
Hz, 1H), 5.13 (dd, J=14.4, 7.1 Hz, 1H), 3.28 (ddd, J=21.0, 13.6,
6.7 Hz, 2H), 1.47 (d, J=6.8 Hz, 9H), 1.33 (s, 9H).
Compound 255 was prepared from tert-butyl
(S)-3-(4-(5-(2H-tetrazol-5-yl)pyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)ben-
zamido)propanoate using General Procedure 12 then General Procedure
8.
Compound 256 was prepared from tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propan-
oate (INT-14) and
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one
using General Procedures 10, 12 and 8.
Compound 257 was prepared from tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propan-
oate (INT-14) and 6-hydroxypyridine-3-boronic acid pinacol ester
using General Procedures 10, 12 and 8.
Compound 258 was prepared from tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13) and
5-(benzyloxy)-2-chloropyrimidine using General Procedure 10,
followed by General Procedure 8.
Compounds 259 and 260 were prepared from tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propan-
oate (INT-14) and the appropriate boronic acid using General
Procedures 10 then 8.
tert-butyl
4-(4-(heptyloxy)phenyl)-3-oxopiperazine-1-carboxylate
##STR00185##
To a stirring solution of 1-bromo-4-(heptyloxy)benzene (447 mg,
1.65 mmol) in dioxane (5 mL) were added tert-butyl
3-oxopiperazine-1-carboxylate (330 mg, 1.65 mmol), copper I iodide
(31.4 mg, 0.17 mmol),
(1R,2R)--N1,N2-dimethylcyclohexane-1,2-diamine (234 mg, 1.65 mmol)
and potassium carbonate (456 mg, 3.30 mmol). The reaction mixture
was heated at 120.degree. C. for 16 h. The reaction mixture was
passed through a plug of celite, eluted with EA (50 mL). The
organics were washed with ammonium chloride (25 mL), water (25 mL)
and brine (25 mL) then dried over MgSO.sub.4 and concentrated to
afford 602 mg (89%) of tert-butyl
4-(4-(heptyloxy)phenyl)-3-oxopiperazine-1-carboxylate. LCMS-ESI
(m/z) calculated for C.sub.22H.sub.34N.sub.2O.sub.4: 390.5; found
319.0 [M+H].sup.+, t.sub.R=2.90 min. (Method 4).
1-(4-(heptyloxy)phenyl)piperazin-2-one
##STR00186##
To tert-butyl 4-(4-(heptyloxy)phenyl)-3-oxopiperazine-1-carboxylate
(540 mg, 1.38 mmol) was added 4M HCl in dioxane (2.07 mL, 8.30
mmol). The reaction mixture was stirred at room temperature for 2
h. The precipitate was filtered, washed with hexane (5 mL) and
dried. The crude product was purified by column chromatography
(79/20/1 DCM/MeOH/NH.sub.4) to afford 325 mg (80%) of
1-(4-(heptyloxy)phenyl)piperazin-2-one as a colorless solid.
LCMS-ESI (m/z) calculated for C.sub.17H.sub.26N.sub.2O.sub.2:
290.4; found 291.0 [M+H].sup.+, t.sub.R=1.49 min. (Method 4).
Compound 261 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phen-
yl)propanoate (INT-12) and 1-(4-(heptyloxy)phenyl)piperazin-2-one
using General Procedures 11 and 8.
Compound 262 was prepared in a similar fashion from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phen-
yl)propanoate (INT-12) and
1-(4-(heptyloxy)phenyl)imidazolidin-2-one using General Procedures
11 and 8.
Compound 263 was prepared using (S)-methyl
2-amino-3-(4-nitrophenyl)propanoate hydrochloride,
4-(tert-butyl)benzoic acid and
1-(4-(heptyloxy)phenyl)piperidin-4-one using General Procedures 7,
14, 15 then 4.
tert-butyl
4-(4-(heptyloxy)phenyl)-4-hydroxypiperidine-1-carboxylate
##STR00187##
To a stirring solution of 1-bromo-4-(heptyloxy)benzene (668 mg,
2.46 mmol) in THF (5 mL) at -78.degree. C. was added butyllithium
(985 .mu.l, 2.46 mmol). After 30 min, a solution of tert-butyl
4-oxopiperidine-1-carboxylate (491 mg, 2.46 mmol) in THF (2 mL) was
added. After 10 min, the cooling bath was removed and the reaction
mixture stirred for 16 h. The reaction mixture was poured onto
NH.sub.4Cl (50 mL) and extracted with Et.sub.2O (3.times.20 mL).
The combined organics were washed with water (20 mL), dried over
MgSO.sub.4 and evaporated. The crude product was purified by column
chromatography (5-70% AcMe in iso-hexanes) to afford 0.4 g (33%) of
tert-butyl
4-(4-(heptyloxy)phenyl)-4-hydroxypiperidine-1-carboxylate. LCMS-ESI
(m/z) calculated for C.sub.23H.sub.37NO.sub.4: 391.5; found 414.0
[M+Na].sup.+, t.sub.R=2.24 min. (Method 4).
4-(4-(heptyloxy)phenyl)piperidine (INT-19)
##STR00188##
To a stirring solution of tert-butyl
4-(4-(heptyloxy)phenyl)-4-hydroxypiperidine-1-carboxylate (388 mg,
0.99 mmol) and triethylsilane (791 .mu.l, 4.95 mmol) in DCM (2 mL)
cooled to -30.degree. C. was slowly added 2,2,2-trifluoroacetic
acid (379 .mu.l, 4.95 mmol) in a drop-wise fashion. The reaction
mixture was allowed to warm slowly and stirring continued for 16 h.
The reaction mixture was poured onto ice-water/NaOH (50 mL/5 mL, 2
M) and extracted with DCM (3.times.20 mL). The combined organic
extracts were washed successively with water (50 mL) and
NaHCO.sub.3 (20 mL), dried over MgSO.sub.4 and evaporated to afford
166 mg (58%) of 4-(4-(heptyloxy)phenyl)piperidine (INT-19) as a
white, waxy solid. LCMS-ESI (m/z) calculated for
C.sub.18H.sub.29NO: 275.4; found 276.0 [M+H].sup.+, t.sub.R=2.88
min. (Method 11).
Compound 264 was prepared using
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phen-
yl)propanoate (INT-12) and 4-(4-(heptyloxy)phenyl)piperidine
(INT-19) using General Procedures 11 then 8.
Compound 265 was prepared in a similar fashion to
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)piperidin-1--
yl)phenyl)propanoic acid (Compound 264) using
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phen-
yl)propanoate (INT-12) and 3-(4-(heptyloxy)phenyl)pyrrolidine using
General Procedures 11 then 8.
Compound 266 was prepared using
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phen-
yl)propanoate (INT-12) and 1-([1,1'-biphenyl]-4-yl)piperazine using
General Procedures 11 then 8.
Compound 267 was prepared using
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phen-
yl)propanoate (INT-12), tert-butyl
4-(4-hydroxyphenyl)piperazine-1-carboxylate and 1-bromoheptane
using General Procedures 12, 8, 11 then 8.
Compound 268 was prepared using
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(((trifluoromethyl)sulfonyl)oxy)phen-
yl)propanoate (INT-12), tert-butyl 1,4-diazepane-1-carboxylate and
1-bromo-4-(heptyloxy)benzene using General Procedures 11, 8, 11
then 8.
Compound 269 was prepared using 5-bromo-2-iodopyridine, tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13) and
(4-(heptyloxy)phenyl)boronic acid using General Procedures 10, 10,
and 8 sequentially.
Compound 270 was prepared using 5-bromo-2-iodopyridine,
(4-(heptyloxy)phenyl)boronic acid and tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13) using General Procedures 10,
10, and 8 sequentially.
Compound 271 was prepared using 5-bromo-2-iodopyrimidine,
(4-(heptyloxy)phenyl)boronic acid and tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13) using General Procedures 10,
10, and 8 sequentially.
Compound 272 was prepared using 2-bromo-5-iodopyrazine,
(4-(heptyloxy)phenyl)boronic acid and tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13) using General Procedures 10,
10, and 8 sequentially.
Compound 273 was prepared using 3-chloro-6-iodopyridazine,
(4-(heptyloxy)phenyl)boronic acid and tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13) using General Procedures 10,
10, and 8 sequentially.
3-(4-bromophenyl)-6-(4-(heptyloxy)phenyl)-1, 2, 4-triazine
(INT-20)
##STR00189##
To a stirring solution of 4-bromobenzohydrazide (1.85 g, 8.62 mmol)
in ethanol (10 mL) was added acetic acid (1 mL). The reaction
mixture was stirred at 60.degree. C. for 30 min then
2-bromo-1-(4-(heptyloxy)phenyl)ethanone (INT-4) (1.35 g, 4.31 mmol)
and sodium acetate (0.389 g, 4.74 mmol) were added and the mixture
heated to reflux for 30 min. The reaction mixture was cooled to
room temperature and the resultant precipitate was filtered and
washed with iso-hexanes (20 mL) then dried. The solid was dissolved
in NMP and heated to 120.degree. C. for 16 h. The crude material
was cooled to room temperature, diluted with Et.sub.2O (4 mL),
filtered, triturated with ethanol (3.times.2 mL), filtered and
dried to afford 241 mg (13%) of
3-(4-bromophenyl)-6-(4-(heptyloxy)phenyl)-1,2,4-triazine (INT-20)
as an orange solid. LCMS-ESI (m/z) calculated for
C.sub.22H.sub.24BrN.sub.3O: 425.1; found 426.3 [M+H].sup.+,
t.sub.R=3.40 min (Method 8).
Compound 274 was prepared in a similar fashion to
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)thiazol-2-yl-
)phenyl)propanoic acid
(Compound 79) using
3-(4-bromophenyl)-6-(4-(heptyloxy)phenyl)-1,2,4-triazine (INT-20)
in place of 2-(4-bromophenyl)-4-(4-(heptyloxy)phenyl)thiazole.
6-(4-bromophenyl)-3-(4-(heptyloxy)phenyl)-1, 2, 4-triazine
(INT-21)
##STR00190##
To a stirring solution of 4-(heptyloxy)benzohydrazide (400 mg, 1.60
mmol) in ethanol (15 mL) was added acetic acid (1 mL). The reaction
mixture was stirred at 60.degree. C. for 30 min then
2-bromo-1-(4-bromophenyl)ethanone (222 mg, 0.80 mmol) and sodium
acetate (72.1 mg, 0.88 mmol) were added and the solution heated to
reflux for 2 h. The reaction mixture was cooled to room temperature
and the resultant crystals were filtered, washed with iso-hexanes
(20 mL) then dried to afford 108 mg (31%) of
6-(4-bromophenyl)-3-(4-(heptyloxy)phenyl)-1,2,4-triazine (INT-21).
LCMS-ESI (m/z) calculated for C.sub.22H.sub.24BrN.sub.3O: 425.1;
found 426.1 [M+H].sup.+, t.sub.R=3.38 min (Method 8).
Compound 275 was prepared in a similar fashion to
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(6-(4-(heptyloxy)phenyl)-1,2,4-triaz-
in-3-yl)phenyl)propanoic acid (Compound 274) using
6-(4-bromophenyl)-3-(4-(heptyloxy)phenyl)-1,2,4-triazine (INT-21)
in place of
3-(4-bromophenyl)-6-(4-(heptyloxy)phenyl)-1,2,4-triazine.
Compound 276 was prepared using
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(6-(4-(heptyloxy)phenyl)-1,2,4-triaz-
in-3-yl)phenyl)propanoic acid (Compound 274) using General
Procedures 7 and 8.
Compounds 277 and 278 were prepared using tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1-
,3,2-dioxaborolan-2-yl)phenyl)propanoate (INT-16) and
5-bromo-2-iodopyridine using General Procedures 10, 10, and 8
sequentially.
Compounds 279 and 280 were prepared using tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1-
,3,2-dioxaborolan-2-yl)phenyl)propanoate (INT-16) and
3-chloro-6-iodopyridazine using General Procedures 10, 10, and 8
sequentially.
Compounds 281 and 282 were prepared using tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1-
,3,2-dioxaborolan-2-yl)phenyl)propanoate (INT-16) and
2-bromo-5-iodopyrazine using General Procedures 10, 10, and 8
sequentially.
Compound 283 was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(6-(4-(heptyloxy)pheny-
l)pyridazin-3-yl)phenyl)propanoic acid (Compound 279) and
tert-butyl glycinate using General Procedures 7 and 8
sequentially.
Compound 284 was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrazin-2-yl)phenyl)propanoic acid (Compound 281) and tert-butyl
glycinate using General Procedures 7 and 8 sequentially.
Compound 285 was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyridin-2-yl)phenyl)propanoic acid (Compound 277) and tert-butyl
glycinate using General Procedures 7 and 8 sequentially.
2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-bromobenzoate
##STR00191##
To a solution of 2-bromo-1-(4-(heptyloxy)phenyl)ethanone (INT-4)
(1.3 g, 4.2 mmol) and 4-bromobenzoic acid (0.70 g, 3.5 mmol) in ACN
(30 mL) was added TEA (0.72 ml, 5.2 mmol). After stirring
overnight, the mixture was poured onto aq. citric acid and EA then
stirred for 10 min before the solid was collected by filtration.
The cake was washed with water and iso-hexanes then dried to
provide 905 mg (57%) of 2-(4-(heptyloxy)phenyl)-2-oxoethyl
4-bromobenzoate. LCMS-ESI (m/z) calculated for
C.sub.22H.sub.25BrO.sub.4: 432.1; found 433.2 [M+H].sup.+,
t.sub.R=3.24 min (Method 8).
2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1H-imidazole
##STR00192##
To a solution of 2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-bromobenzoate
(905 mg, 2.09 mmol) intoluene (6 ml) was added CH.sub.3COONH.sub.4
(1600 mg, 20.9 mmol). After heating overnight at 115.degree. C.,
the reaction mixture was diluted with aq. NaHCO.sub.3 and extracted
into DCM. The organic layers were combined, dried over MgSO.sub.4,
filtered, and the solvent was removed under reduced pressure. The
crude reaction mixture was purified by chromatography (EA/hexanes)
to provide 370 mg (33%) of
2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1H-imidazole. LCMS-ESI
(m/z) calculated for C.sub.22H.sub.25BrN.sub.2O: 412.1; found 413.2
[M+H].sup.+, t.sub.R=2.33 min (Method 8).
2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)met-
hyl)-1H-imidazole
##STR00193##
To a solution of
2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1H-imidazole (370 g, 900
mmol) in DMF (4 ml) was added NaH (40 mg, 980 mmol). After 2 h,
2-(trimethylsilyl)ethoxymethyl chloride (160 g, 990 mmol) in THF (2
ml) was added dropwise and reaction mixture was stirred overnight.
The reaction mixture was diluted with EA and washed with aq.
NaHCO.sub.3. The organics were dried over MgSO.sub.4, filtered, and
the solvent was removed under reduced pressure. The crude product
was purified by chromatography (EA/hexane) to afford 32 mg (65%) of
2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-imidazole as a tan solid. LCMS-ESI (m/z) calculated for
C.sub.28H.sub.39BrN.sub.2O.sub.2Si: 542.2; found 543.3 [M+H].sup.+,
t.sub.R=3.35 min (Method 8).
(S)-methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)-1--
((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)propanoate
##STR00194##
A stirred suspension of zinc (68 mg, 1.03 mmol) in DMF (2 mL) was
treated with I.sub.2 (12 mg, 0.05 mmol). After the color
disappeared, ((R)-methyl
2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (110 mg, 0.34 mmol)
and further I.sub.2 (12 mg, 0.05 mmol) were added. After 30 min,
the mixture was de-gassed then
2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)me-
thyl)-1H-imidazole (170 mg, 0.31 mmol),
dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (7 mg,
0.02 mmol) and Pd.sub.2(dba).sub.3 (8 mg, 7.8 .mu.mol) were added.
After further de-gassing, DMF (2 mL) was added and the reaction
mixture was heated at 50.degree. C. overnight. The reaction mixture
purified by column chromatography (EA/hexane) to provide 55 mg
(25%) of (S)-methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)-1-((2-(trime-
thylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)propanoate as a
colorless oil. LCMS-ESI (m/z) calculated for
C.sub.37H.sub.55N.sub.3O.sub.6Si: 665.9; found 666.4 [M+H].sup.+,
t.sub.R=3.10 min (Method 8).
(S)-methyl
2-amino-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)--
propanoate
##STR00195##
(S)-methyl
2-amino-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoate
was prepared from (S)-methyl
2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-(heptyloxy)phenyl)-1-((2-(trime-
thyl silyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)propanoate using
General Procedure 8. LCMS-ESI (m/z) calculated for
C.sub.26H.sub.33N.sub.3O.sub.3: 435.6; found 436.3 [M+H].sup.+,
t.sub.R=1.43 min (Method 8).
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol--
2-yl)phenyl)propanoic acid hydrochloride (Compound 286)
##STR00196##
To a solution of 4-(tert-butyl)benzoic acid (25 mg, 0.14 mmol),
(S)-methyl
2-amino-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoate
(55 mg, 0.13 mmol), and TEA (53 .mu.l, 0.38 mmol) in DMF (1 mL) was
added HATU (53 mg, 0.14 mmol). The reaction mixture was stirred at
room temperature for 2 h, diluted in DCM, and washed aq.
NaHCO.sub.3. The organic layer was dried, concentrated and purified
by chromatography (EA/hexane) to provide 14 mg (17%) of methyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-
-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for
C.sub.37H.sub.45N.sub.3O.sub.4: 595.8; found 596.4 [M+H].sup.+,
t.sub.R=2.33 min. (Method 8).
The isolated ester intermediate was deprotected using General
Procedure 4 to provide 14 mg (17.5%) of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-
-2-yl)phenyl)propanoic acid hydrochloride (Compound 286) as a light
tan solid. LCMS-ESI (m/z) calculated for
C.sub.36H.sub.43N.sub.3O.sub.4: 581.8; found 582.4 [M+H].sup.+,
t.sub.R=6.56 min (Method 9).
4-bromo-1-(4-(heptyloxy)phenyl)-1H-imidazole
##STR00197##
Into a vial was charged (4-(heptyloxy)phenyl)boronic acid (1.00 g,
4.24 mmol), 4-bromo-1H-imidazole (0.31 g, 2.1 mmol),
Cu-(TMEDA).sub.2(OH).sub.2Cl.sub.2 (0.10 g, 0.21 mmol) and DCM (12
ml). After stirring at room temperature for 42 h, the mixture was
purified by chromatography (EA/hexane) to provide 80 mg of impure
product. Further purification by chromatography (CAN/DCM) provided
42 mg (6%) of 4-bromo-1-(4-(heptyloxy)phenyl)-1H-imidazole as a
colourless oil. LCMS-ESI (m/z) calculated for
C.sub.16H.sub.21BrN.sub.2O: 336.1; found 337.1 [M+H].sup.+,
t.sub.R=2.71 min (Method 8).
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4-(heptyloxy)phenyl)-1H-imidazol--
4-yl)phenyl)propanoic acid (Compound 287)
##STR00198##
Prepared using General Procedure 10. Into a vial containing
tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13) (96 mg, 0.19 mmol) and
4-bromo-1-(4-(heptyloxy)phenyl)-1H-imidazole (64 mg, 0.19 mmol) in
2/2/1 THF/CAN/H.sub.2O (3 mL) was added Na.sub.2CO.sub.3 (40 mg,
0.38 mmol). The reaction mixture was degassed and Pd(dppf)Cl.sub.2
(14 mg, 0.02 mmol) was added. After heating at 120.degree. C. for
30 min in a microwave reactor, the mixture was diluted with EA,
washed with aq. NaHCO.sub.3, dried over MgSO.sub.4 and
concentrated. Purification by chromatography (EA/hexanes) provided
14 mg (12%) of the intermediate tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4-(heptyloxy)phenyl)-1H-imidazol-
-4-yl)phenyl)propanoate as a white solid.
The intermediate was deprotected according to General Procedure 8
to provide 9 mg (8%) of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4-(heptyloxy)phenyl)-1H-imidazol-
-4-yl)phenyl)propanoic acid (Compound 287) as a white solid.
LCMS-ESI (m/z) calculated for C.sub.36H.sub.43N.sub.3O.sub.4:
581.3; found 582.2 [M+H].sup.+, t.sub.R=8.33 min (Method 9).
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4'-methyl-[1,1'-biphenyl]-4-yl)-1-
H-pyrazol-4-yl)phenyl)propanoic acid (Compound 288)
##STR00199##
Prepared using General Procedure 10. Into a vial containing
tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13) (100 mg, 0.20 mmol) and
4-bromo-1-(4'-methyl-[1,1'-biphenyl]-4-yl)-1H-pyrazole (63 mg,
0.201 mmol) in 2/1 ACN/H.sub.2O (3 mL) was added sat aq.
NaHCO.sub.3 (670 .mu.L, 0.60 mmol). The reaction mixture was
degassed and Pd(dppf)Cl.sub.2 (15 mg, 0.02 mmol) was added. After
heating at 120.degree. C. for 60 min in a microwave reactor, the
mixture was diluted with DCM, washed with aq. NaHCO.sub.3, passed
through a phase separation cartridge, and concentrated.
Purification by chromatography (EA/hexane) provided 58 mg (47%) of
the intermediate tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4'-methyl-[1,
1'-biphenyl]-4-yl)-1H-pyrazol-4-yl)phenyl)propanoate as a white
solid. LCMS-ESI (m/z) calculated for
C.sub.40H.sub.43N.sub.3O.sub.3: 613.8; found 614.0 [M+H].sup.+,
t.sub.R=3.02 min (Method 8). The intermediate was stirred in 4M
HCl/dioxane for 132 h and filtered. The resulting solid was washed
with hexane to provide 13 mg of solid product. The filtrate was
loaded onto a strong anion exchange (SAX) column, washed with MeOH,
and eluted with 5% AcOH in MeOH. The elution liquors were combined
with the trituration solid and concentrated in vacuo to afford 18
mg (32%) of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(1-(4'-methyl-[1,1'-biphenyl]-4-yl)--
1H-pyrazol-4-yl)phenyl)propanoic acid (Compound 288) as a white
solid. LCMS-ESI (m/z) calculated for
C.sub.36H.sub.35N.sub.3O.sub.3: 557.3; found 558.0 [M+H].sup.+,
t.sub.R=9.37 min (Method 9).
methyl
2-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)acetate
##STR00200##
Prepared using General Procedure 7. To a solution of methyl
2-amino-2-(4-bromophenyl)acetate, HCl (730 mg, 2.6 mmol),
5-(tert-butyl)thiophene-2-carboxylic acid (480 mg, 2.6 mmol) and
TEA (1090 .mu.l, 7.8 mmol) in DMF (10 mL) was added HATU (1090 mg,
2.9 mmol). After stirring overnight, the reaction mixture was
diluted with EA (100 mL) and washed with 1M HCl (100 mL) and brine.
The organic layer was dried over Mg.sub.2SO.sub.4, concentrated,
and purified by chromatography (EA/hexane) to provide 900 mg (76%)
of methyl
2-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)acetate
as a white powder. LCMS-ESI (m/z) calculated for
C.sub.18H.sub.20BrNO.sub.3S: 410.3; found 412.0 [M+2].sup.+,
t.sub.R=2.71 min (Method 8).
methyl
2-(5-(tert-butyl)thiophene-2-carboxamido)-2-(4-(4,4,5,5-tetramethyl-
-1,3,2-dioxaborolan-2-yl)phenyl)acetate
##STR00201##
Prepared using General Procedure 10. A solution of
2-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)acetate
(900 mg, 2.2 mmol), KOAc (650 mg, 6.6 mmol) and
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (670
mg, 2.6 mmol) in DMSO (10 mL) at 40.degree. C. was de-gassed.
PdCl.sub.2dppf (80 mg, 0.11 mmol) was added and the mixture was
heated at 100.degree. C. for 3 h. The reaction mixture was purified
by chromatography (EA/hexane with 1% TEA) to provide 491 mg (41%)
of methyl
2-(5-(tert-butyl)thiophene-2-carboxamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-
-dioxaborolan-2-yl)phenyl)acetate. LCMS-ESI (m/z) calculated for
C.sub.24H.sub.32BNO.sub.5S: 457.4; found 458.0 [M+H].sup.+,
t.sub.R=2.89 min (Method 8).
2-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxami-
do)acetic acid
##STR00202##
Prepared using General Procedure 10. A mixture of methyl
2-(5-(tert-butyl)thiophene-2-carboxamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-
-dioxaborolan-2-yl)phenyl)acetate (320 mg, 0.71 mmol) and
5-bromo-2-iodopyrimidine (220 mg, 0.78 mmol) in THF (2 mL) and ACN
(2 mL) was treated with saturated aq. NaHCO.sub.3 (1600 .mu.l, 1.40
mmol) and de-gassed (N.sub.2 bubbling). PdCl.sub.2dppf (26 mg, 0.04
mmol) was added and the mixture was heated at 120.degree. C. for 30
min in a microwave reactor. The mixture was poured onto H.sub.2O
(30 mL), acidified with AcOH and extracted with EA (3.times.15 mL).
The combined organics were dried over MgSO.sub.4, evaporated, and
purified by chromatography (EA/hexane with 1% AcOH) to provide 160
mg (46%) of
2-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxam-
ido)acetic acid as a white solid. LCMS-ESI (m/z) calculated for
C.sub.21H.sub.20BrN.sub.3O.sub.3S: 473.0; found 474.0 [M+H].sup.+,
t.sub.R=2.68 min (Method 8).
2-(5-(tert-butyl)thiophene-2-carboxamido)-2-(4-(5-(4-(heptyloxy)phenyl)pyr-
imidin-2-yl)phenyl)acetic acid (Compound 289)
##STR00203##
Prepared using General Procedure 10. A solution of
2-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxam-
ido)acetic acid (160 mg, 0.34 mmol), (4-(heptyloxy)phenyl)boronic
acid (94 mg, 0.40 mmol) and sat aq. NaHCO.sub.3 (930 .mu.l, 0.84
mmol) in ACN (1.5 mL) and THF (1.5 mL) was degassed (N.sub.2
bubbling). PdCl.sub.2(dppf) (262 mg, 0.34 mmol) was added and the
reaction mixture was heated at 110.degree. C. in a microwave
reactor for 50 min. The reaction was partitioned between EA and
H.sub.2O. The organic layer was dried over MgSO.sub.4, filtered,
concentrated and purified by chromatography (EA/hexane with 1%
AcOH) to afford 113 mg (55%) of
2-(5-(tert-butyl)thiophene-2-carboxamido)-2-(4-(5-(4-(heptyloxy)phenyl)py-
rimidin-2-yl)phenyl)acetic acid (Compound 289) as a white solid.
LCMS-ESI (m/z) calculated for C.sub.34H.sub.39N.sub.3O.sub.4S:
585.3; found 586.0 [M+H].sup.+, t.sub.R=3.37 min (Method 9).
(S)--N-(1-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-oxop-
ropan-2-yl)-4-(tert-butyl)benzamide
##STR00204##
A solution of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) (245 mg, 0.413 mmol) in DMF
(5 mL) was treated with NH.sub.4Cl (180 mg, 3.3 mmol), DIEA (760
.mu.l, 4.1 mmol) and HATU (170 mg, 0.4 mmol). After stirring
overnight, the reaction mixture was diluted with EA (50 mL), washed
with aq. 0.5 M HCl (100 mL) and brine (20 mL), then dried over
MgSO.sub.4 and concentrated. The residue was re-slurried from ACN
(4 mL) to afford 204 mg (77%) of
(S)--N-(1-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-oxo-
propan-2-yl)-4-(tert-butyl)benzamide as a fine white solid.
LCMS-ESI (m/z) calculated for C.sub.37H.sub.44N.sub.4O.sub.3:
592.3; found 593.0 [M+H].sup.+, t.sub.R=3.43 min (Method 6).
(S)-methyl
3-(4-(tert-butyl)benzamido)-4-(4-hydroxyphenyl)butanoate
##STR00205##
Prepared using General Procedure 7. A solution of (S)-methyl
3-amino-4-(4-hydroxyphenyl)butanoate hydrochloride (2.1 g, 8.7
mmol), 4-(tert-butyl)benzoic acid (1.6 g, 9.0 mmol) and DIEA (3.5
ml, 18.8 mmol) in DMF (20 mL) and DCM (20 mL) was treated with HATU
(3.3 g, 8.5 mmol). After 1 h, the mixture was poured onto 1M HCl
(100 mL) and extracted with EA (3.times.50 mL). The combined
organic extracts were washed successively with 1M HCl (50 mL),
water (50 mL) and brine (20 mL), then dried over MgSO.sub.4 and
concentrated. The resulting residue was purified by chromatography
(EA/hexane) to provide 2.3 g (72%) of (S)-methyl
3-(4-(tert-butyl)benzamido)-4-(4-hydroxyphenyl)butanoate as white
needles. LCMS-ESI (m/z) calculated for C.sub.22H.sub.27NO: 369.4,
found 370.0 [M+H].sup.+, t.sub.R=2.52 min (Method 6).
(S)-methyl
3-(4-(tert-butyl)benzamido)-4-(4-(((trifluoromethyl)sulfonyl)ox-
y)-phenyl)butanoate
##STR00206##
Prepared using General Procedure 9. A stirred solution of
(S)-methyl 3-(4-(tert-butyl)benzamido)-4-(4-hydroxyphenyl)butanoate
(2.30 g, 6.3 mmol) in DCM (25 mL) was treated with DIEA (1.4 ml,
7.6 mmol) then
1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide
(2.5 g, 6.9 mmol). After 18 h, the reaction mixture was diluted
with DCM (100 mL), H.sub.2O (50 mL) and NaHCO.sub.3 (75 mL) and
stirred for 1 h. The organic layer was isolated, washed with
NaHCO.sub.3 (100 mL), dried over MgSO.sub.4, concentrated, and
purified by chromatography (EA/hexane) to provide 2.5 g (75%) of
(S)-methyl
3-(4-(tert-butyl)benzamido)-4-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)b-
utanoate as a thick oil. LCMS-ESI (m/z) calculated for
C.sub.23H.sub.26F.sub.3NO.sub.6S: 501.5, found 502 [M+H].sup.+,
t.sub.R=3.20 min (Method 6).
(S)-methyl
3-(4-(tert-butyl)benzamido)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)phenyl)butanoate
##STR00207##
To a vial under a N.sub.2 atmosphere were added
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (530
mg, 2.1 mmol), (S)-methyl
3-(4-(tert-butyl)benzamido)-4-(4-(((trifluoromethyl)sulfonyl)oxy)phenyl)b-
utanoate (810 mg, 1.6 mmol), KOAc (280 mg, 4.8 mmol) and DMSO (14
mL). The solution was degassed. Pd(dppf)Cl.sub.2 (59 mg, 0.08 mmol)
was added and the solution was heated to 80.degree. C. for 6 h. The
reaction mixture was cooled to room temperature, diluted with EA
(100 mL) and washed with sat aq. NaHCO.sub.3 (50 ml) and brine (50
mL). The organic layer was dried over MgSO.sub.4, concentrated and
purified by chromatography (EA/hexane) to afford 446 mg (57%) of
(S)-methyl
3-(4-(tert-butyl)benzamido)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl) as a colorless crystalline solid. LCMS-ESI (m/z)
calculated for C.sub.28H.sub.38BNO.sub.5: 479.4, found 480.3
[M+H].sup.+, t.sub.R=2.86 min (Method 6).
(S)-methyl
4-(4-(5-bromopyrimidin-2-yl)phenyl)-3-(4-(tert-butyl)benzamido)-
-butanoate
##STR00208##
Prepared using General Procedure 10. Into a vial were
added(S)-methyl
3-(4-(tert-butyl)benzamido)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl) (390 mg, 0.81 mmol), 5-bromo-2-iodopyrimidine (240 mg,
0.85 mmol), Na.sub.2CO.sub.3 (170 mg, 1.6 mmol), THF (1.5 mL), ACN
(1.5 mL) and H.sub.2O (0.75 mL). The solution was degassed and
PdCl.sub.2(dppf) (60 mg, 0.08 mmol) was added. The reaction mixture
was heated in a microwave reactor at 110.degree. C. for 60 min. The
sample was cooled, diluted with EA (50 mL), and washed with sat
aq.NaHCO.sub.3 (30 mL). The organic layers were dried over
MgSO.sub.4, filtered, concentrated, and purified by chromatography
(EA/hexane) to afford 205 mg (49%) of (S)-methyl
4-(4-(5-bromopyrimidin-2-yl)phenyl)-3-(4-(tert-butyl)benzamido)butanoate
as a colourless solid. LCMS-ESI (m/z) calculated for
C.sub.26H.sub.28BrN.sub.3O.sub.3: 510.4, found 512.2 [M+H].sup.+,
t.sub.R=2.77 min (Method 6).
(S)-3-(4-(tert-butyl)benzamido)-4-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-y-
l)phenyl)butanoic acid (Compound 291)
##STR00209##
Prepared using General Procedures 10 and 4. Into a vial were added
(S)-methyl
4-(4-(5-bromopyrimidin-2-yl)phenyl)-3-(4-(tert-butyl)benzamido)butanoate
(180 mg, 0.35 mmol), (4-(heptyloxy)phenyl)boronic acid (98 mg, 0.41
mmol), Na.sub.2CO.sub.3 (73 mg, 0.69 mmol), ACN (1.2 mL), THF (1.2
mL) and H.sub.2O (0.7 mL). The solution was degassed,
Pd(dppf)Cl.sub.2 (25 mg, 0.03 mmol) was added, and the reaction
mixture was heated in a microwave reactor at 110.degree. C. for 80
min. The reaction mixture was diluted with EA (50 mL) and washed
with sat aq. NaHCO.sub.3 (30 mL). The organics layer was dried over
MgSO.sub.4, concentrated, and purified by chromatography
(EA/hexane) to afford 44 mg of methyl ester intermediate. The solid
was dissolved in THF (1 mL) and 1M LiOH (1 mL). The solution was
stirred at ambient temperature for 1 h, concentrated, and 1M HCl
(1.5 mL) was added. The solid was collected by filtration, washing
with water (2.times.5 mL) and hexane (2.times.5 mL) to provide 19
mg (9%) of
(S)-3-(4-(tert-butyl)benzamido)-4-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)butanoic acid (Compound 291) as a colorless solid.
LCMS-ESI (m/z) calculated for C.sub.38H.sub.45N.sub.3O.sub.4:
607.8, found 608.4 [M+H].sup.+, t.sub.R=10.99 min (Method 10).
5-bromo-2-chloro-4-methoxypyrimidine
##STR00210##
To a stirred solution of 5-bromo-2,4-dichloropyrimidine (500 mg,
2.19 mmol) in MeOH (5 mL) was added a 30% solution of sodium
methoxide (0.40 mL, 2.26 mmol). The reaction mixture was stirred at
room temperature for 2 h then concentrated. The residue was
dissolved in water (5 mL) and extracted with EA (3.times.5 mL). The
combined organic layer was washed with brine, dried over MgSO.sub.4
and concentrated to afford 432 mg (88%) of
5-bromo-2-chloro-4-methoxypyrimidine as white solid. LCMS-ESI (m/z)
calculated for C.sub.5H.sub.4BrClN.sub.2O: 223.4; found 224.2
[M+H].sup.+, t.sub.R=7.66 min. (Method 2).
5-bromo-2-iodo-4-methoxypyrimidine
##STR00211##
Prepared using General Procedure 16: To a stirred solution of
5-bromo-2-chloro-4-methoxypyrimidine (100 mg, 0.447 mmol) in 57%
aq. HI (1.0 mL) was added sodium iodide (125 mg, 0.838 mmol). The
reaction mixture was stirred at 40.degree. C. for 16 h, cooled,
then quenched with NaHCO.sub.3 (5 mL) and extracted with EA
(3.times.5 mL). The combined organics were washed with brine, dried
over MgSO.sub.4 and concentrated to afford 22.0 mg (16%) of
5-bromo-2-iodo-4-methoxypyrimidine as an off-white solid. LCMS-ESI
(m/z) calculated for C.sub.5H.sub.4BrIN.sub.2O: 314.9; found 315.9
[M+H].sup.+, t.sub.R=8.22 min. (Method 2). .sup.1H NMR (400 MHz,
DMSO) .delta. 8.25 (s, 1H), 4.07 (s, 3H).
tert-butyl
(S)-3-(4-(5-bromo-4-methoxypyrimidin-2-yl)phenyl)-2-(4-(tert-bu-
tyl)benzamido)propanoate
##STR00212##
Prepared using General Procedure 10: A mixture of tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13) (30.0 mg, 0.06 mmol),
5-bromo-2-iodo-4-methoxypyrimidine (22.3 mg, 0.07 mmol), and sodium
carbonate (12.5 mg, 0.12 mmol) in acetonitrile (0.80 mL), THF (0.80
mL) and H.sub.2O (0.40 mL) was degassed for 10 min.
Pd(dppf)Cl.sub.2:CH.sub.2Cl.sub.2 (5 mg, 0.005 mmol) was added and
the reaction mixture heated at 110.degree. C. in a microwave for 30
min. Once cooled, the reaction was diluted with NaHCO.sub.3 (5 mL),
extracted with EA (3.times.5 mL) and the combined organics dried
over MgSO.sub.4 and concentrated. The residue was purified by
column chromatography (EA/hexanes) to afford 20.0 mg (60%) of
tert-butyl
(S)-3-(4-(5-bromo-4-methoxypyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzam-
ido)propanoate as a white solid. LCMS-ESI (m/z) calculated for
C.sub.29H.sub.34BrN.sub.3O.sub.4: 568.5; found 514.2
[M-tBu+H].sup.+, t.sub.R=11.0 min. (Method 2).
tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-4-
-methoxypyrimidin-2-yl)phenyl)propanoate
##STR00213##
Prepared using General Procedure 10: A mixture of tert-butyl
(S)-3-(4-(5-bromo-4-methoxypyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzam-
ido)propanoate (18.0 mg, 0.031 mmol), (4-(heptyloxy)phenyl)boronic
acid (10.0 mg, 0.042 mmol) and sodium carbonate (8.97 mg, 0.084
mmol) in acetonitrile (0.80 mL), THF (0.80 mL) and H.sub.2O (0.40
mL) was degassed for 10 min. Pd(dppf)Cl.sub.2:CH.sub.2Cl.sub.2
(3.09 mg, 0.003 mmol) was added and the reaction mixture heated at
110.degree. C. in a microwave for 30 min. Once cooled, the reaction
was diluted with NaHCO.sub.3 (5 mL) and extracted with EA
(3.times.5 mL). The combined organics were dried over MgSO.sub.4
and concentrated. The residue was purified by column chromatography
(EA:hexanes) to afford 20.0 mg (60%) of tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-4-methoxypy-
rimidin-2-yl)phenyl)propanoate as pale yellow solid. LCMS-ESI (m/z)
calculated for C.sub.42H.sub.53N.sub.3O.sub.5: 679.8; no ion
observed, t.sub.R=13.83 min. (Method 2).
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-4-methoxypyr-
imidin-2-yl)phenyl)propanoic acid (Compound 292)
##STR00214##
Prepared using General Procedure 8: A solution of tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl-4-methoxypyr-
imidin-2-yl)phenyl)propanoate (20.0 mg, 0.029 mmol) in DCM (1 mL)
was treated with TFA (0.350 mL). The reaction mixture was stirred
at room temperature for 12 h. The solvent was concentrated and the
product was purified preparative HPLC to yield 15.0 mg (82%) of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-4-methoxypy-
rimidin-2-yl)phenyl)propanoic acid (Compound 292) as pale yellow
solid. LCMS-ESI (m/z) calculated for
C.sub.38H.sub.45N.sub.3O.sub.5: 623.8; no ion observed,
t.sub.R=12.17 min. (Method 2).
Compound 293 was prepared using tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13) and
5-bromo-2-chloro-N,N-dimethylpyrimidin-4-amine using General
Procedures 10, 10 and 8 sequentially.
Compound 294 was prepared using tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13) and
5-bromo-2-iodo-4-methylpyridine using General Procedures 10, 10 and
8 sequentially.
5-bromo-2-iodo-4-(trifluoromethyl)pyridine
##STR00215##
Prepared using General Procedure/7: To a stirred a solution of
5-bromo-2-chloro-4-(trifluoromethyl)pyridine (150 mg, 0.576 mmol)
in acetonitrile (2 mL) was added sodium iodide (518 mg, 3.45 mmol).
The reaction mixture was heated to 40.degree. C. and acetyl
chloride (26.0 mg, 0.345 mmol) was added. The reaction mixture was
stirred at 40.degree. C. for 90 min. Once cooled, the reaction was
quenched with NaHCO.sub.3 (5 mL) and extracted with EA (3.times.5
mL). The combined organics were washed with brine (10 mL), dried
over MgSO.sub.4 and concentrated to give 80.0 mg (40%) of
5-bromo-2-iodo-4-(trifluoromethyl)pyridine as a white crystalline
solid which was used in the subsequent step without purification.
LCMS-ESI (m/z) calculated for C.sub.6H.sub.2BrF.sub.3IN: 351.9;
found 352.5 [M+H].sup.+, t.sub.R=3.91 min. (Method 1).
Compound 295 was prepared by employing tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13) and
5-bromo-2-iodo-4-(trifluoromethyl)pyridine using General Procedures
10, 10 and 8 sequentially.
(S)-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoyl)glycine (Compound 297)
##STR00216##
Prepared using General Procedures 7 and 8: To a solution of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) (185 mg, 0.312 mmol),
tert-butyl 2-aminoacetate hydrochloride (52.2 mg, 0.312 mmol), and
DIEA (163 .mu.l, 0.935 mmol) in DMF (3 mL) was added HATU (124 mg,
0.327 mmol). The mixture was stirred for 1 h at room temperature.
The crude material was diluted in EA (50 mL), washed with saturated
aqueous sodium bicarbonate (20 mL) and brine (20 mL). The organic
layer was dried over MgSO.sub.4, filtered, and the solvent removed
under reduced pressure. The crude product was purified by
chromatography (EA/hexanes) to afford the intermediate tert-butyl
ester (110 mg).
The tert-butyl ester was dissolved in DCM (1 mL) and TFA (2 mL) was
added. The solution was stirred at room temperature for 3 h and the
solvent was removed under reduced pressure. The crude mixture was
dissolved in DMSO (0.8 mL) and precipitated by the addition of
water (3 mL). The precipitate was filtered, washed with water (3
mL) and hexane (2.times.2 mL) to yield 58 mg (28%) of
(S)-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-
-yl)phenyl)propanoyl)glycine (Compound 297) as a colorless solid.
LCMS-ESI (m/z) calculated for C.sub.39H.sub.46N.sub.4O.sub.5:
650.4; found 651.4 [M+H].sup.+, t.sub.R=10.43 min (Method 10). The
chiral purity was calculated at 92% e.e. (Chiral Method). .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 12.62 (s, 1H), 9.15 (s, 2H), 8.60
(d, J=8.6 Hz, 1H), 8.49-8.40 (m, 1H), 8.35-8.25 (m, 2H), 7.84-7.70
(m, 4H), 7.58-7.49 (m, 2H), 7.48-7.41 (m, 2H), 7.16-7.02 (m, 2H),
4.90-4.75 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.93-3.75 (m, 2H), 3.25
(dd, J=13.8, 3.8 Hz, 1H), 3.09 (dd, J=13.7, 11.2 Hz, 1H), 1.79-1.68
(m, 2H), 1.51-1.21 (m, 17H), 0.94-0.80 (m, 3H).
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin--
2-yl)phenyl)propanamido)propanoic acid (Compound 298)
##STR00217##
Prepared using General Procedures 7 and 8: HATU (116 mg, 0.31 mmol)
was added to a stirring solution of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) (173 mg, 0.29 mmol),
tert-butyl 3-aminopropanoate hydrochloride (53 mg, 0.29 mmol) and
DIEA (153 .mu.l, 0.87 mmol) in DMF (3 mL). The crude material was
diluted in EA (50 mL), washed with saturated aqueous sodium
bicarbonate (20 mL) and brine (20 mL). The organic layer was dried
over MgSO.sub.4, filtered, and the solvent removed under reduced
pressure. The crude product was purified by chromatography
(EA/hexanes) to afford the intermediate tert-butyl ester (122
mg).
The tert-butyl ester was dissolved in DCM (1 mL) and TFA (2 mL) was
added. The reaction mixture was stirred at room temperature for 3 h
and the solvent was removed under reduced pressure. The crude
mixture was dissolved in DMSO (0.8 mL) and precipitated by the
addition of water (3 mL). The precipitate was filtered, washed with
water (3 mL) and hexane (2.times.2 mL) to yield 48 mg (25%) of
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)propanamido)propanoic acid (Compound 298) as a
colorless solid. LCMS-ESI (m/z) calculated for
C.sub.40H.sub.48N.sub.4O.sub.5: 664.4; found 665.4 [M+H].sup.+,
t.sub.R=10.36 min (Method 10). The chiral purity was calculated at
92% e.e. (Chiral Method, isocratic with 40% Solvent A, 60% Solvent
B). .sup.1H NMR (400 MHz, DMSO-d6) .delta.12.26 (s, 1H), 9.15 (s,
2H), 8.51 (d, J=8.5 Hz, 1H), 8.40-8.25 (m, 2H), 8.25-8.14 (m, 1H),
7.96-7.65 (m, 4H), 7.65-7.36 (m, 4H), 7.28-6.99 (m, 2H), 4.84-4.64
(m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.32-3.24 (m, 2H), 3.17 (dd,
J=13.7, 4.4 Hz, 1H), 3.06 (dd, J=13.7, 10.4 Hz, 1H), 2.41 (t, J=6.9
Hz, 2H), 1.81-1.68 (m, 2H), 1.50-1.20 (m, 17H), 0.88 (t, J=6.7 Hz,
3H).
(S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)--
1-(methylsulfonamido)-1-oxopropan-2-yl)benzamide (Compound 299)
##STR00218##
To a solution of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) (78.0 mg, 0.13 mmol),
methanesulfonamide (20.0 mg, 0.21 mmol), and DMAP (16.1 mg, 0.13
mmol) in DMF (1.5 mL) was added EDC (40.3 mg, 0.21 mmol) and the
solution stirred overnight at room temperature. The reaction
mixture was diluted in EA (50 mL), washed with aqueous saturated
sodium bicarbonate (2.times.20 mL) and brine (20 mL). The organic
layer was dried over MgSO.sub.4, filtered, and the solvent removed
under reduced pressure. The crude product was purified by
chromatography (hexane/EA) to afford 36 mg (40%) of
(S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-
-1-(methyl sulfonamido)-1-oxopropan-2-yl)benzamide (Compound 299)
as a colorless solid. LCMS-ESI (m/z) calculated for
C.sub.38H.sub.46N.sub.4O.sub.5S: 670.3; found 671.3 [M+H].sup.+,
t.sub.R=11.01 min (Method 10).
Compounds 300-304 were prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) using General Procedures 3
or 7 followed by 4 or 8.
Compounds 305-317 were prepared from
(S)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-2-(4-isopropylben-
zamido)propanoic acid (Compound 94) using General Procedures 3 or 7
followed by 4 or 8.
Compound 318 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(hexyloxy)phenyl)pyrimidin-2-y-
l)phenyl)propanoic acid (Compound 225) using General Procedures 7
followed by 8.
(S)-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoyl)glycine (Compound 319)
##STR00219##
Prepared using General Procedures 7 and 4: TEA (93 .mu.l, 0.67
mmol) was added to a solution of
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)-phen-
yl)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) (100 mg,
0.167 mmol), methyl 2-aminoacetate hydrochloride (23.03 mg, 0.18
mmol) and HATU (76 mg, 0.20 mmol) in DMF (2 mL). The solution was
stirred at room temperature for 18 h. The reaction mixture was
diluted with EA (25 mL) and washed with saturated aqueous
NaHCO.sub.3 (2.times.25 mL) and 1 M HCl (2.times.25 mL). The
organic phase was dried over MgSO.sub.4, filtered, and
concentrated. The solid was purified by chromatography (EA/hexanes)
to afford the methyl ester intermediate as a colorless solid.
The solid was dissolved in THF (3 mL) and 1 M LiOH (333 .mu.l, 0.33
mmol) was added. The resultant yellow solution was stirred at room
temperature for 1 h. The reaction mixture was acidified to pH 1
using 1M HCl and the THF removed in vacuo. The residue was
suspended in water and the mixture filtered under vacuum. The solid
was azeotroped with MeOH and dried in a vacuum oven to afford 48 mg
(44%) of
(S)-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phen-
yl)pyrimidin-2-yl)phenyl)-propanoyl)glycine (Compound 319) as a
yellow solid. LCMS-ESI (m/z) calculated for
C.sub.37H.sub.44N.sub.4O.sub.5S: 656.3; found 657.0 [M+H].sup.+,
t.sub.R=10.34 min (Method 10). The chiral purity was calculated at
95% e.e. (Chiral Method). .sup.1H NMR (400 MHz, DMSO-d6) .delta.
12.61 (s, 1H), 9.16 (s, 2H), 8.62 (d, J=8.7 Hz, 1H), 8.51-8.41 (m,
1H), 8.36-8.26 (m, 2H), 7.84-7.75 (m, 2H), 7.68 (d, J=3.8 Hz, 1H),
7.55-7.43 (m, 2H), 7.14-7.05 (m, 2H), 6.92 (d, J=3.8 Hz, 1H),
4.84-4.72 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.89-3.73 (m, 2H), 3.22
(dd, J=13.9, 3.7 Hz, 1H), 3.10-2.96 (m, 1H), 1.78-1.66 (m, 2H),
1.31 (s, 17H), 0.94-0.81 (m, 3H).
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)-pyrimidin-2-yl)phenyl)propanoyl)-L-glutamine (Compound 320)
##STR00220##
Prepared using General Procedures 7 and 8: To a stirred solution of
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)-propanoic acid (Compound 192) (250 mg,
0.42 mmol), (S)-tert-butyl 2,5-diamino-5-oxopentanoate
hydrochloride (109 mg, 0.46 mmol) and TEA (145 .mu.l, 1.04 mmol) in
DMF (4 mL) was added HATU (190 mg, 0.50 mmol) and the reaction
mixture was stirred at room temperature for 2 h. The reaction
mixture was diluted with EA (50 mL), washed with 1M HCl (50 mL) and
brine (100 mL), dried over MgSO.sub.4, and concentrated.
The crude product was dissolved in DCM (5 mL) and TFA (3 mL) was
added. After 3 h, toluene (10 mL) was added and the solvent
removed. The compound was purified by preparative HPLC to afford 78
mg (25%) of
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phen-
yl)pyrimidin-2-yl)phenyl)propanoyl)-L-glutamine (Compound 320) as a
white powder. LCMS-ESI (m/z) calculated for
C.sub.40H.sub.49N.sub.5O.sub.6S: 727.3; found 728.0 [M+H].sup.+,
t.sub.R=10.71 min (Method 10). The chiral purity was 90% d.e.
(Chiral Method). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.15 (s,
2H), 8.56 (d, J=8.6 Hz, 1H), 8.42-8.34 (m, 1H), 8.34-8.27 (m, 2H),
7.84-7.75 (m, 2H), 7.66 (d, J=3.9 Hz, 1H), 7.54-7.48 (m, 2H), 7.32
(s, 1H), 7.12-7.04 (m, 2H), 6.90 (d, J=3.8 Hz, 1H), 6.77 (s, 1H),
4.81-4.65 (m, 1H), 4.19-4.11 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.20
(dd, J=14.1, 3.5 Hz, 1H), 3.07-2.96 (m, 1H), 2.24-2.09 (m, 2H),
2.06-1.93 (M, 1H), 1.90-1.79 (m, 1H), 1.78-1.68 (m, 2H), 1.47-1.20
(m, 17H), 0.93-0.82 (m, 3H).
Compounds 321-326 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)-propanoic acid (Compound 192) using
General Procedures 3 or 7 followed by 4 or 8.
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin--
2-yl)phenyl)propanoic acid (INT-22)
##STR00221##
Prepared using General Procedure 8. To a stirred solution of
(S)-tert-butyl
2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate
(INT-8) (6.4 g, 10.26 mmol) in DCM (30 mL) was added TFA (20 mL)
and the mixture was stirred at room temperature for 3 h. Toluene
(50 mL then 2.times.30 mL) was added and the solvent as removed
under vacuum. The material was sonicated in DCM (20 mL) and
acetonitrile (30 mL) was added. The DCM was partially removed under
a flow of air until a precipitate began to appear. The suspension
was stirred for a further 2 h and the yellow solid was isolated by
filtration and washed with additional iso-hexanes (100 mL). The
solid was dried under suction then at under vacuum at 40.degree. C.
overnight to afford 5.5 g (90%)
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)propanoic acid (INT-22) as a yellow solid. LCMS-ESI
(m/z) calculated for C.sub.34H.sub.37N.sub.3O.sub.5: 567.3; found
568.3 [M+H].sup.+, t.sub.R=10.11 min (Method 10).
tert-butyl
((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)pheny-
l)-pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate (INT-23)
##STR00222##
Prepared using General Procedure 7. To a stirred solution of
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)-propanoic acid (INT-22) (1000 mg, 1.762 mmol) and
(R)-tert-butyl 2-aminopropanoate HCl (352 mg, 1.938 mmol) in DMF (8
mL). The solution was cooled to 0.degree. C. and TEA (737 .mu.l,
5.28 mmol) was added. To this mixture was slowly added HATU (804
mg, 2.114 mmol) over 5 mins then the reaction mixture was allowed
to warm to room temperature. The reaction mixture was diluted with
EA (150 mL) and washed with 1M HCl (100 mL) then brine (100 mL).
The organic layer was isolated and dried over MgSO.sub.4. The
solvents were removed to give a white solid and ACN (50 mL) was
added and the suspension was sonicated. The fine suspension was
stirred for 30 mins then filtered and washed with iso-hexanes to
afford 881 mg (70.5%) of tert-butyl
((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidi-
n-2-yl)phenyl)propanoyl)-D-alaninate (INT-23) as a white powder.
LCMS-ESI (m/z) calculated for C.sub.41H.sub.50N.sub.4O.sub.6:
694.4; no m/z observed, t.sub.R=3.39 min (Method 11). The chiral
purity was calculated at >99% e.e. (Chiral Method).
tert-butyl
((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl-
)propanoyl)-D-alaninate (INT-24)
##STR00223##
Prepared using General Procedure 18: To a stirred solution of
tert-butyl
((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidi-
n-2-yl)phenyl)propanoyl)-D-alaninate (INT-23) (860 mg, 1.238 mmol)
in THF (30 mL) was added palladium on carbon (10 wt %) as a slurry
in EtOH (4 mL). To this mixture was added acetic acid (1 mL) and
the reaction mixture was hydrogenated at 4 bar pressure at room
temperature. The reaction mixture was diluted with THF (50 mL) and
filtered through Celite. The crude product was loaded onto a column
in 5% AcOH in MeOH/THF. The column was washed with MeOH/THF/DCM and
then the product was eluted with 0.7 M ammonia in MeOH/THF/DCM. The
resultant mixture was concentrated in vacuo to afford 565 mg (77%)
of tert-butyl
((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl-
)-D-alaninate (INT-24) as a yellow solid. LCMS-ESI (m/z) calculated
for C.sub.33H.sub.44N.sub.4O.sub.4: 560.3; no m/z observed,
t.sub.R=2.61 min (Method 11).
tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(hept-
yloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate
##STR00224##
Prepared using General Procedure 7. To a stirred solution of
tert-butyl
((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl-
)-D-alaninate (418 mg, 0.75 mmol),
5-(tert-butyl)thiophene-2-carboxylic acid (137 mg, 0.75 mmol) in
DMF (8 mL) was added TEA (208 .mu.l, 1.49 mmol). The mixture was
cooled to 0.degree. C. and HATU (298 mg, 0.78 mmol) was added in 2
portions over 5 mins. The mixture was stirred at room temperature
for 2 h. The reaction mixture was diluted with EA (150 mL) and
washed with saturated aqueous NaHCO.sub.3 (100 mL), 1N HCl (100
mL), and brine (100 mL). The organic layer was dried over
MgSO.sub.4 then concentrated. The crude product was purified by
chromatography 0-30% ACN in DCM to afford 382 mg (69%) of
tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phen-
yl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate as a white solid.
LCMS-ESI (m/z) calculated for C.sub.42H.sub.54N.sub.4O.sub.5S:
726.4; no m/z observed, t.sub.R=3.47 min (Method 11).
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)-pyrimidin-2-yl)phenyl)propanoyl)-D-alanine (Compound 327)
##STR00225##
Prepared using General Procedure 8. To a stirred solution of
tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phen-
yl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate (375 mg, 0.495
mmol) in DCM (8 mL) was added TFA (4 mL) and the mixture was
stirred at room temperature for 3 h. The reaction mixture was
azetroped with toluene (2.times.30 mL) to give a viscous oily
solid. DMSO (5 mL) was added and the solution was sonicated. To
this solution was added water (60 mL) and the mixture was sonicated
for 5 mins then stirred at room temperature for 20 mins. The white
solid was isolated by filtration and washed with additional water
(20 mL) and isohexanes (30 mL). The material was dried under
vacuum, suspended in ACN (20 mL), then diluted with diethyl ether
(30 mL) and stirred for 20 mins. The suspension was filtered and
the wet solid was dried under vacuum to give 189.3 mg (55%) of
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phen-
yl)pyrimidin-2-yl)phenyl)propanoyl)-D-alanine (Compound 327) as a
white powder. LCMS-ESI (m/z) calculated for
C.sub.38H.sub.46N.sub.4O.sub.5S: 670.3; found 671.0 [M+H].sup.+,
t.sub.R=13.32 min (Method 10). The chiral purity was calculated at
>99% e.e. (Chiral Method). .sup.1NMR (400 MHz, DMSO-d6) .delta.
12.64 (s, 1H), 9.16 (s, 2H), 8.56 (d, J=8.8 Hz, 1H), 8.48 (d, J=7.4
Hz, 1H), 8.35-8.26 (m, 2H), 7.84-7.76 (m, 2H), 7.70 (d, J=3.9 Hz,
1H), 7.54-7.45 (m, 2H), 7.13-7.05 (m, 2H), 6.92 (d, J=3.8 Hz, 1H),
4.86-4.77 (m, 1H), 4.29-4.18 (m, 1H), 4.03 (t, J=6.5 Hz, 2H),
3.20-3.10 (m, 1H), 3.08-2.94 (m, 1H), 1.80-1.68 (m, 2H), 1.51-1.22
(m, 20H), 0.94-0.83 (m, 3H).
(S)-tert-butyl
1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimi-
din-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate (INT-25)
##STR00226##
Prepared using General Procedure 7. A stirred solution of
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)propanoic acid (INT-22) (419 mg, 0.738 mmol),
(S)-tert-butyl pyrrolidine-2-carboxylate HCl (153 mg, 0.738 mmol)
and TEA (257 .mu.l, 1.845 mmol) in DMF (6 mL) was cooled to
0.degree. C. and HATU (295 mg, 0.775 mmol) was slowly added over 5
minutes. The reaction was stirred at room temperature for 2 h, then
diluted with 1M citric acid (30 mL) and iso-hexanes (20 mL). EA
(100 mL) was added and the organic layer was isolated, washed with
brine (100 mL), dried with MgSO.sub.4. The solvent was removed and
the crude product was purified by chromatography 0-20% ACN in DCM
to afford 436 mg (81%) of (S)-tert-butyl
1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimi-
din-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate (INT-25) as a
viscous oil. LCMS-ESI (m/z) calculated for
C.sub.43H.sub.52N.sub.4O.sub.6: 720.4; no m/z observed,
t.sub.R=11.45 min (Method 10).
(S)-tert-butyl
1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propano-
yl)pyrrolidine-2-carboxylate (INT-26)
##STR00227##
Prepared using General Procedure 18: A solution of (S)-tert-butyl
1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimi-
din-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate (INT-25) (436
mg, 0.6 mmol) in THF (25 mL) was hydrogenated in the H-Cube using a
10% Pd/C CatCart at 60.degree. C. (Full hydrogen, 1 mL/min). The
reaction mixture was passed over the catalyst a second time at
65.degree. C. The solvent was removed to give 307 mg (83%) of
(S)-tert-butyl
1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propano-
yl)pyrrolidine-2-carboxylate (INT-26) as a white powder. LCMS-ESI
(m/z) calculated for C.sub.35H.sub.46N.sub.4O.sub.4: 586.4; found
587.4 [M+H].sup.+, t.sub.R=6.99 min (Method 10).
(S)-tert-butyl
1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)ph-
enyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate
##STR00228##
Prepared using General Procedure 7: A stirred solution of
(S)-tert-butyl
1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propano-
yl)pyrrolidine-2-carboxylate (306 mg, 0.522 mmol) and
5-(tert-butyl)thiophene-2-carboxylic acid (106 mg, 0.574 mmol) in
DMF (6 mL) was added TEA (145 .mu.l, 1.043 mmol), cooled to
0.degree. C., then HATU (218 mg, 0.574 mmol) was slowly added over
5 minutes. The reaction was stirred at room temperature for 2 h,
then diluted with EA (70 mL), washed with saturated aqueous
NaHCO.sub.3 (70 mL) and brine (100 mL). The solvent was dried over
MgSO.sub.4 and removed. The crude product was purified by
chromatography 0-30% ACN in DCM to afford 363 mg (92%) of
(S)-tert-butyl
1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)ph-
enyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate as a
sticky solid. LCMS-ESI (m/z) calculated for
C.sub.44H.sub.56N.sub.4O.sub.5S: 752.4; no m/z observed,
t.sub.R=11.99 min (Method 10).
(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy-
)-phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylic
acid (Compound 328)
##STR00229##
Prepared using General Procedure 8. To a stirred solution of
(S)-tert-butyl
1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)ph-
enyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylate (350
mg, 0.465 mmol) in DCM (5 mL) was added TFA (5 mL) and stirred at
room temperature for 2 h. The reaction mixture was diluted with
toluene (10 mL) and solvent removed. The residue was dissolved in
EA (50 mL), THF (5 mL) and acetone (10 mL) and washed with a
mixture of saturated aqueous NaHCO.sub.3 (10 mL) and brine (40 mL).
The aqueous layer was removed and acetic acid (5 mL) was added. The
organic layer was washed with brine (50 mL) and dried over
MgSO.sub.4. The solvent was removed and residual acetic acid was
removed under high vacuum overnight. The material was dissolved in
DCM (5 mL) and ACN (5 mL) was added. The material was stirred under
a flow of air for 1 hour and the suspension was filtered and the
solid washed with additional ACN (5 mL) and iso-hexanes (20 mL) to
give 134 mg (41%) of
(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptylox-
y)phenyl)-pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylic
acid (Compound 328) as a yellow powder. LCMS-ESI (m/z) calculated
for C.sub.40H.sub.48N.sub.4O.sub.5S: 696.3; found 697.3
[M+H].sup.+, t.sub.R=10.59 min (Method 10). The chiral purity was
calculated at >93% e.e. (Chiral Method). .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 12.47 (s, 1H), 9.17 (s, 2H), 8.74 (d, J=8.3 Hz,
1H), 8.38-8.27 (m, 2H), 7.86-7.76 (m, 2H), 7.71 (d, J=3.9 Hz, 1H),
7.57-7.48 (m, 2H), 7.14-7.02 (m, 2H), 6.92 (d, J=3.9 Hz, 1H),
4.94-4.86 (m, 1H), 4.33-4.27 (m, 1H), 4.04 (t, J=6.5 Hz, 2H),
3.86-3.74 (m, 1H), 3.69-3.59 (m, 1H), 3.19-3.01 (m, 2H), 2.24-2.13
(m, 1H), 2.01-1.84 (m, 3H), 1.80-1.68 (m, 2H), 1.52-1.23 (m, 17H),
0.93-0.85 (m, 3H).
Compounds 329-350 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 3 or 7 followed by 4 or 8.
Compounds 351-368 were prepared from
(S)-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)-2-(5-(tert-butyl-
)thiophene-2-carboxamido)propanoic acid (Compound 165) using
General Procedures 7 followed by 4 or 8.
Compound 369 was prepared from
(S)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-2-(1-isopropyl-1H-
-pyrazole-4-carboxamido)propanoic acid (Compound 139) using General
Procedures 7 followed by 8.
Compound 370 was prepared from
(S)-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)-2-(1-isopropyl-1-
H-pyrazole-4-carboxamido)propanoic acid (Compound 167) using
General Procedures 7 followed by 8.
Compound 371 was prepared from
(S)-2-(5-(tert-butyl)thiazole-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl-
)pyrimidin-2-yl)phenyl)propanoic acid (Compound 142) using General
Procedures 7 followed by 8.
Compound 372 was prepared from
(S)-2-(1-(tert-butyl)-1H-pyrazole-4-carboxamido)-3-(4-(5-(4-(heptyloxy)ph-
enyl)pyrimidin-2-yl)phenyl)propanoic acid (Compound 143) using
General Procedures 7 followed by 8.
Compound 373 was prepared from
(R)-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)-2-(5-(tert-butyl-
)thiophene-2-carboxamido)propanoic acid (Compound 182) using
General Procedures 7 followed by 8.
Compounds 374-379 were prepared from
(R)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 193) using General
Procedures 3 or 7 followed by 4 or 8.
Compound 380 was prepared from
(R)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 191) using General Procedures 7
followed by 8.
(S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)--
1-((2-(methylsulfonamido)-2-oxoethyl)amino)-1-oxopropan-2-yl)benzamide
(Compound 381)
##STR00230##
TEA (32.1 .mu.l, 0.23 mmol) was added to a suspension of
(S)-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-
-yl)phenyl)propanoyl)glycine (Compound 297) (75.0 mg, 0.11 mmol),
methanesulfonamide (12.1 mg, 0.13 mmol), HATU (52.6 mg, 0.14 mmol)
and DMAP (1.41 mg, 0.01 mmol) were combined in DCM (2 mL). The
resultant yellow suspension was stirred at room temperature for 3
h. The reaction mixture was washed with saturated aqueous
NaHCO.sub.3 (2 mL) and the mixture passed through a phase
separation cartridge. The organic phase was concentrated in vacuo
to afford a yellow solid. The crude product was purified by
chromatography (EA/1% AcOH in hexanes) to afford 9 mg (11%)
(S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2yl)phenyl)--
1-((2-(methyl
sulfonamido)-2-oxoethyl)amino)-1-oxopropan-2-yl)benzamide (Compound
381) as a yellow solid. LCMS-ESI (m/z) calculated for
C.sub.40H.sub.49N.sub.5O.sub.6S: 727.3; found 728.0 [M+H].sup.+,
t.sub.R=10.51 min (Method 10).
Compounds 382-390 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using the
appropriate combination of General Procedures 4, 7, and 8 as
needed.
ethyl
2-amino-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)p-
henyl)propanoate
##STR00231##
To a stirred solution of ethyl 2-((diphenylmethylene)amino)acetate
(300 mg, 1.12 mmol) in anhydrous THF (3 mL) at -78.degree. C. was
added 0.5 M KHMDS in toluene (2.46 mL, 1.23 mmol). After stirring
for 15 min,
2-(4-(bromomethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
e (353 mg, 1.12 mmol) was added. The reaction mixture was stirred
at -78.degree. C. for 3 h and warmed to -20.degree. C. To the
mixture was added 6 N Hydrochloric acid (0.5 mL) and the mixture
was stirred overnight at room temperature. The reaction mixture was
diluted with water (5 mL) and 1 N HCl (5 mL) and then extracted
with diethyl ether. The aqueous layer was basified with 1N NaOH and
then extracted with EtOAc (3.times.10 mL). The combined organic
extract was washed with water, brine and then dried over
MgSO.sub.4. Filtration and concentration gave 177 mg (46%) of ethyl
2-amino-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)propanoate which was used in the next step without purification.
LCMS-ESI (m/z) calculated for C.sub.17H.sub.25BFNO.sub.4: 337.2;
found 338.2 [M+H].sup.+, t.sub.R=2.78 min (Method 1).
Compound 391 was prepared using ethyl
2-amino-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-
)propanoate and 5-(tert-butyl)thiophene-2-carbonyl chloride using
General Procedure 3 followed by treatment with
5-(4-(tert-butyl)phenyl)-2-iodopyrimidine and General Procedure
10.
Compounds 392-396 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using, as
needed, the appropriate combination of General Procedures 4, 7, and
8.
(S)-2-(4-(3-(tert-butoxy)-2-(4-(tert-butyl)benzamido)-3-oxopropyl)phenyl)--
pyrimidine-5-carboxylic acid
##STR00232##
Prepared using General Procedure 10. Into an oven-dried vial
containing lithium formate (58 mg (1.1 mmol) in DMF (5 mL) were
added DIEA (400 .mu.L, 2.2 mmol) and acetic anhydride (210 .mu.L,
2.2 mmol). After stirring for 1 h, the reaction mixture was
degassed by N.sub.2 bubbling. A second, degassed solution
containing tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propan-
oate (INT-14) (200 mg, 0.4 mmol) and PdCl.sub.2(dppf) (27 mg, 0.04
mmol) in DMF (5 mL) was added via cannula. The resulting mixture
was heated for 1 h at 120.degree. C. in a microwave reactor. The
reaction mixture was diluted with 10% citric acid and extracted
with EA. The organic extract was dried (Na.sub.2SO.sub.4),
concentrated, and purified by chromatography (EA/hexane) to provide
166 mg (88%) of
(S)-2-(4-(3-(tert-butoxy)-2-(4-(tert-butyl)benzamido)-3-oxopropyl)phenyl)-
pyrimidine-5-carboxylic acid as a brown solid. LCMS-ESI (m/z)
calculated for C.sub.29H.sub.33BN.sub.3O.sub.5: 503.6; found 504.2
[M+H].sup.+, t.sub.R=3.87 min (Method 1). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.24 (s, 2H), 8.42 (d, J=8.2 Hz, 2H), 7.75 (t,
J=11.9 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H),
6.91 (t, J=11.5 Hz, 1H), 5.12 (dd, J=12.9, 5.5 Hz, 1H), 3.32 (qd,
J=13.8, 5.4 Hz, 2H), 1.50 (s, 9H), 1.29 (d, J=29.8 Hz, 9H).
tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(2-heptanoylhydrazine-1-
-carbonyl)pyrimidin-2-yl)phenyl)propanoate
##STR00233##
Prepared using General Procedure 7. Into a stirring solution of
(S)-2-(4-(3-(tert-butoxy)-2-(4-(tert-butyl)benzamido)-3-oxopropyl)phenyl)-
pyrimidine-5-carboxylic acid (50 mg, 0.10 mmol) in DCM (2 mL) were
added EDC (34 mg, 0.20 mmol), DMAP (3 mg, 0.02 mmol) and
heptanehydrazide (16 mg, 0.11 mmol). After 18 h, the reaction
mixture was diluted with NaHCO.sub.3 and extracted with DCM
(2.times.). The organic layers were combined, dried
(Na.sub.2SO.sub.4), concentrated and purified by chromatography
(EA/Hexane) to provide 38 mg (61%) of tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(2-heptanoylhydrazine-1-carbonyl)-
pyrimidin-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for
C.sub.36H.sub.47BN.sub.5O.sub.5: 629.8; no m/z observed,
t.sub.R=3.84 min (Method 1). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.17 (s, 2H), 8.42 (d, J=8.2 Hz, 2H), 7.69 (d, J=8.4 Hz,
2H), 7.43 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 6.70 (d, J=7.3
Hz, 1H), 5.01 (dd, J=12.6, 5.8 Hz, 1H), 3.41-3.20 (m, 2H), 2.35 (t,
J=7.5 Hz, 2H), 1.81-1.61 (m, 2H), 1.59 (d, J=14.0 Hz, 2H), 1.45 (s,
4H), 1.42-1.22 (m, 18H), 0.88 (t, J=6.8 Hz, 3H).
tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,3,4-thiadiaz-
ol-2-yl)pyrimidin-2-yl)phenyl)propanoate
##STR00234##
To a solution of tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(2-heptanoylhydrazine-1-carbonyl)-
pyrimidin-2-yl)phenyl)propanoate (38 mg, 0.06 mmol) in THF (1.5 mL)
was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane
2,4-disulfide (24 mg, 0.06 mmol). After 1.5 h, the reaction mixture
was concentrated and purified by preparative HPLC to provide 10 mg
(27%) of tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,3,4-thiadiazol-2-yl)py-
rimidin-2-yl)phenyl) propanoate. LCMS-ESI (m/z) calculated for
C.sub.36H.sub.45N.sub.5O.sub.5S: 627.9; no m/z observed,
t.sub.R=3.89 min (Method 1). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.29 (s, 2H), 8.44 (d, J=8.2 Hz, 2H), 7.75-7.66 (m, 2H),
7.50-7.41 (m, 2H), 7.35 (d, J=8.3 Hz, 2H), 6.68 (d, J=7.3 Hz, 1H),
5.02 (dd, J=12.7, 5.6 Hz, 1H), 3.33 (qd, J=13.8, 5.5 Hz, 2H),
3.26-3.15 (m, 2H), 1.87 (dt, J=15.3, 7.6 Hz, 2H), 1.46 (d, J=5.1
Hz, 10H), 1.41-1.23 (m, 14H), 0.96-0.85 (m, 3H).
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,3,4-thiadiazol-2-yl)pyr-
imidin-2-yl)phenyl)propanoic acid (Compound 397)
##STR00235##
Prepared using General Procedure 8 from tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(5-hexyl-1,3,4-thiadiazol-2-yl)py-
rimidin-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for
C.sub.32H.sub.37N.sub.5O.sub.3S: 571.4; found 571.7 [M+H].sup.+,
t.sub.R=10.66 min (Method 2). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.30 (d, J=2.6 Hz, 2H), 8.48 (d, J=8.2 Hz, 2H), 7.67 (d,
J=8.4 Hz, 2H), 7.43 (dd, J=13.7, 8.3 Hz, 4H), 6.61 (d, J=6.8 Hz,
1H), 5.20-5.04 (m, 1H), 3.45 (ddd, J=36.2, 13.9, 5.6 Hz, 2H), 3.20
(t, J=7.6 Hz, 2H), 1.95-1.75 (m, 2H), 1.54-1.36 (m, 2H), 1.39-1.19
(m, 13H), 0.91 (t, J=7.0 Hz, 3H).
(R)-tert-butyl
2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)propanamido)propanoate
##STR00236##
Prepared using General Procedure 7. A stirred solution of
(R)-tert-butyl
2-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propana-
mido)propanoate (122 mg, 0.218 mmol), 4-(tert-butyl)benzoic acid
(38.8 mg, 0.218 mmol) and TEA (60.7 .mu.l, 0.435 mmol) in DMF (4
mL) was cooled to 0.degree. C. and HATU (87 mg, 0.228 mmol) was
slowly added over 5 minutes. The reaction was stirred at room
temperature for 2 h, then diluted with EA (100 mL), washed with
saturated aqueous NaHCO.sub.3 (100 mL) and brine (100 mL). The
solvent was dried over MgSO.sub.4 and removed. The crude product
was purified by chromatography 0-30% ACN in DCM to afford 123 mg
(78%) of (R)-tert-butyl
2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)propanamido)propanoate as a white solid. LCMS-ESI
(m/z) calculated for C.sub.44H.sub.56N.sub.4O.sub.5: 720.4; no m/z
observed, t.sub.R=3.47 min (Method 11).
(R)-2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimi-
din-2-yl)phenyl)propanamido)propanoic acid (Compound 398)
##STR00237##
Prepared using General Procedure 8. To a stirred solution of
(R)-tert-butyl
2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)propanamido)propanoate (120 mg, 0.166 mmol) in DCM (4
mL) was added TFA (3 mL) and stirred for 2 h. The reaction mixture
was diluted with toluene (15 mL) and solvent removed. DMSO (3 mL)
was added and the solution was sonicated. This solution was added
to vigorously stirring water (30 mL) and the white solid was
isolated by filtration and washed with additional ACN (10 mL). The
material was dried under high vacuum for 24 h to afford 75 mg (66%)
of
(R)-2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrim-
idin-2-yl)phenyl)propanamido)propanoic acid (Compound 398) as a
white powder. LCMS-ESI (m/z) calculated for
C.sub.40H.sub.48N.sub.4O.sub.5: 664.4; found 665.0 [M+H].sup.+,
t.sub.R=12.33 min (Method 10). The chiral purity was calculated at
>99% e.e. (Chiral Method). .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 12.64 (s, 1H), 9.15 (s, 2H), 8.52 (d, J=8.7 Hz, 1H), 8.45
(d, J=7.4 Hz, 1H), 8.35-8.20 (m, 2H), 7.85-7.68 (m, 4H), 7.56-7.50
(m, 2H), 7.49-7.39 (m, 2H), 7.14-7.03 (m, 2H), 4.93-4.80 (m, 1H),
4.38-4.17 (m, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.22-3.12 (m, 1H),
3.12-3.02 (m, 1H), 1.81-1.67 (m, 2H), 1.53-1.24 (m, 20H), 0.95-0.80
(m, 3H).
Compounds 399, 400, and 409 were prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) using, as needed, the
appropriate combination of General Procedures 4, 7, 8, and 18.
Compounds 401-408 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl-
)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using, as
needed, the appropriate combination of General Procedures 4, 7, 8,
and 18.
(S)-4-amino-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(h-
eptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)butanoic acid
(Compound 410)
##STR00238##
Prepared using General Procedures 7,4, and 8: A stirring solution
of
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) (25 mg, 0.042
mmol), (S)-methyl 2-amino-4-((tert-butoxycarbonyl)amino)butanoate
hydrochloride (12 mg, 0.042 mmol), and TEA (0.015 mL, 0.105 mmol)
at 0.degree. C. was treated with HATU (17 mg, 0.046 mmol) in DMF (1
mL). The solution was stirred at room temperature for 18 h. The
reaction mixture was diluted with DCM (5 mL) and washed with
saturated aqueous NaHCO.sub.3 (5 mL), water (5 mL), and brine (5
mL). The organic phase was dried over MgSO.sub.4, filtered, and
concentrated to afford the methyl ester intermediate. The ester was
dissolved in THF (2 mL) and MeOH (1 mL) and 1 N aqueous NaOH (0.1
ml, 0.1 mmol) was added. The solution was stirred at 60.degree. C.
for 5 h. The reaction mixture was concentrated then dissolved in
DCM (0.5 mL) and treated with 1N HCl in ether (0.42 mL, 0.42 mmol).
The reaction was stirred at 27.degree. C. for 18 h. The compound
was purified by preparative HPLC to afford 21 mg (60.0%) of
(S)-4-amino-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(-
heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)butanoic acid
(Compound 410) as the trifluoroacetate salt. LCMS-ESI (m/z)
calculated for C.sub.39H.sub.49N.sub.5O.sub.5S: 699.4; found 700.3
[M+H].sup.+, t.sub.R=9.24 min (Method 12). .sup.1H NMR (400 MHz,
DMSO) .delta. 12.95 (s, 1H), 9.15 (s, 2H), 8.63-8.55 (m, 2H), 8.32
(d, J=8.1 Hz, 2H), 7.78 (d, J=8.7 Hz, 2H), 7.76-7.63 (m, 4H), 7.51
(d, J=8.2 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 6.91 (d, J=3.7 Hz, 1H),
4.87-4.66 (m, 1H), 4.50-4.31 (m, 1H), 4.03 (t, J=6.5 Hz, 2H),
3.23-3.12 (m, 1H), 3.12-3.00 (m, 1H), 2.95-2.77 (m, 2H), 2.18-2.02
(m, 1H), 2.02-1.84 (m, 1H), 1.83-1.64 (m, 2H), 1.50-1.38 (m, 2H),
1.38-1.14 (m, 15H), 0.87 (t, J=6.7 Hz, 3H).
Compounds 411, 412, 414-416, 424-432, 438, and 439 were prepared
from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using, as
needed, the appropriate combination of General Procedures 4, 7, 8,
and 18.
Compounds 413, 417, 418, and 440 were prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) using, as needed, the
appropriate combination of General Procedures 4, 7, 8, and 18.
Compounds 419-423 and 435 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) in a similar
fashion to
(S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phen-
yl)-1-((2-(methylsulfonamido)-2-oxoethyl)amino)-1-oxopropan-2-yl)benzamide
(Compound 381).
Compounds 433, 436, and 437 were prepared from
(R)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (R-Compound 85) using General Procedures 7
and 8.
Compound 434 was prepared from methyl
(S)-2-(N-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy-
)phenyl)pyrimidin-2-yl)phenyl)propanoyl)sulfamoyl)acetate (Compound
422) using General Procedure 4.
Compounds 441 and 442 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 3 and 8.
Compound 443 was prepared from tert-butyl
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-y-
l)phenyl)propanamido)propanoate using General Procedures 12 then
8.
Compounds 444-455 were prepared using, as needed, the appropriate
combination of General Procedures 4, 7, 8, and 18.
Compounds 456-458 were prepared from tert-butyl
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-y-
l)phenyl)propanamido)propanoate using General Procedures 12 then
8.
Compounds 459-464 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using, as
needed, the appropriate combination of General Procedures 4, 7, and
8.
Compounds 465-466 were prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) using, as needed, the
appropriate combination of General Procedures 4, 7, and 8.
2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin--
2-yl)phenyl)propanamido)-3-(1H-1,2,4-triazol-1-yl)propanoic acid
(Compound 467)
##STR00239##
Prepared using General Procedure 7 and then 4.
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (90 mg, 0.152 mmol) and (S)-methyl
2-amino-3-(1H-1,2,4-triazol-1-yl)propanoate (25.8 mg, 0.152 mmol)
in DMF (2.5 mL) was added TEA (52.8 .mu.l, 0.379 mmol) and then
cooled to 0.degree. C. To this mixture was added HATU (57.6 mg,
0.152 mmol) and left at room temperature for 2 h. The reaction
mixture was quenched by the addition of 0.1 M Citric acid (aq. 15
mL) and the solid precipitated was allowed to slurry for 30 mins.
The solid was filtered, washed with water (10 mL), isohexanes (10
mL) and then dried. Then the solid was dissolved in mixture of THF
(4 mL) and MeOH (2 mL). To this solution was added 2M aq. NaOH (380
.mu.L, 0.76 mmol) and the mixture was stirred vigorously at room
temperature for 1 h. The reaction mixture was diluted with 0.1 M
aq. citric acid (20 mL) and stirred for 1 h. The solid formed was
filtered and washed with water (10 mL) and isohexanes (10 mL). The
crude product was purified by column chromatography (0-20% MeOH in
EA) to afford 12 mg (11%) of
2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)propanamido)-3-(1H-1,2,4-triazol-1-yl)propanoic acid
(Compound 467) as a white powder. LCMS-ESI (m/z) calculated for
C.sub.42H.sub.49N.sub.7O.sub.5: 731.9; no m/z observed,
t.sub.R=9.75 min (Method 10). .sup.1H NMR (400 MHz, DMSO-d6)
.delta.3.21 (s, 1H), 9.20 (s, 2H), 8.70 (d, J=8.1 Hz, 0.5H), 8.60
(dd, J 8.4, 4.6 Hz, 1H), 8.56 (d, J=7.8 Hz, 0.5H), 8.52 (d, J=7.1
Hz, 1H), 8.37-8.34 (m, 2H), 8.01 (d, J=6.9 Hz, 1H), 7.85-7.82 (m,
2H), 7.80-7.78 (m, 2H), 7.56-7.49 (m, 4H), 7.14 (d, J=8.9 Hz, 2H),
4.87-4.74 (m, 2H), 4.71-4.55 (m, 2H), 4.08 (t, J=6.5 Hz, 2H),
3.24-2.97 (m, 2H), 1.82-1.75 (m, 2H), 1.51-1.29 (m, 17H), 0.95-0.91
(m, 3H).
Compounds 468 and 469 were prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) using, as needed, the
appropriate combination of General Procedures 4, 7, and 8.
Compound 470 was prepared from (S)-tert-butyl
2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoate
(INT-9) using General Procedures 7 and 8.
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propano-
ic acid (INT-27)
##STR00240##
Prepared using General Procedure 8. LCMS-ESI (m/z) calculated for
C.sub.24H.sub.24BrN.sub.3O.sub.3: 482.3; found 481.1 [M-H].sup.+,
t.sub.R=2.6 min (Method 15), and 98.7% e.e. (Chiral Method,
isocratic with 2% Solvent A, 98% Solvent B). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.87 (s, 2H), 8.32 (d, J=8.3 Hz, 2H), 7.64 (d,
J=8.5 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.3 Hz, 2H), 6.64
(d, J=6.9 Hz, 1H), 5.16 (dd, J=12.7, 5.7 Hz, 1H), 3.42 (ddd,
J=38.8, 14.0, 5.7 Hz, 2H), 1.32 (s, 9H).
tert-butyl
(S)-3-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)-be-
nzamido)propanamido)propanoate (INT-28)
##STR00241##
Prepared using General Procedure 7. A stirring solution of
.beta.-alanine tert-butyl ester hydrochloride (4.9 g, 27.4 mmol),
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propan-
oic acid (12.0 g, 24.9 mmol) and DIEA (11.1 mL, 62.0 mmol) in DMF
(200 mL) was cooled to 0.degree. C. A solution of HATU (9.9 g, 26.1
mmol) in DMF (75 mL) was added dropwise over 20 min. The reaction
mixture was allowed to warm to room temperature over 2 h, then
diluted with EA and washed with NaHCO.sub.3 (sat aq). The aqueous
fraction was back-extracted with EA. The combined organic fractions
were dried (Na.sub.2SO.sub.4) then concentrated onto celite and
purified by column chromatography (EA/hexane) to provide 11 g (65%)
of tert-butyl
(S)-3-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)pro-
panamido)propanoate (INT-28). LCMS-ESI (m/z) calculated for
C.sub.31H.sub.37BrN.sub.4O.sub.4; 609.6; found 610.2 [M+H].sup.+,
t.sub.R=3.99 min (Method 15), and 87.1% e.e. (Chiral Method,
isocratic with 20% Solvent A, 80% Solvent B). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.8.80 (s, 2H), 8.32 (t, J=6.5 Hz, 2H), 7.74-7.62
(m, 2H), 7.41 (d, J=8.5 Hz, 2H), 7.35 (t, J=7.9 Hz, 2H), 6.91 (d,
J=7.7 Hz, 1H), 6.53 (t, J=5.9 Hz, 1H), 4.93-4.81 (m, 1H), 3.52-3.34
(m, 2H), 3.34-3.14 (m, 2H), 2.46-2.24 (m, 2H), 1.34 (d, J=5.2 Hz,
9H), 1.31 (d, J=5.2 Hz, 9H).
tert-butyl
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)-py-
rimidin-2-yl)phenyl)propanamido)propanoate (INT-29)
##STR00242##
Prepared using General Procedure 10 from tert-butyl
(S)-3-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)pro-
panamido)propanoate and 4-hydroxyphenyl boronic acid. LCMS-ESI
(m/z) calculated for C.sub.37H.sub.42BN.sub.4O.sub.5: 622.8; found
621.3 [M-H].sup.+, t.sub.R=3.53 min. (Method 15), and 80.1% e.e.
(Chiral Method, isocratic with 20% Solvent A, 80% Solvent B).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.96 (s, 2H), 8.42 (d,
J=8.0 Hz, 2H), 7.70 (d, J=8.2 Hz, 2H), 7.56-7.32 (m, 6H), 6.95 (d,
J=8.2 Hz, 2H), 6.82 (d, J=7.6 Hz, 1H), 6.35 (s, 1H), 4.88 (d, J=6.9
Hz, 1H), 3.46 (s, 2H), 3.39-3.12 (m, 2H), 2.48-2.15 (m, 2H), 1.36
(s, 9H), 1.33 (s, 9H).
Compound 471 was prepared from tert-butyl
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-y-
l)phenyl)propanamido)propanoate using General Procedures 12 then
8.
tert-butyl
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-((5-methylhexyl)o-
xy)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate
##STR00243##
Prepared using General Procedure 12 from tert-butyl
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-y-
l)phenyl)propanamido)propanoate and 1-bromo-5-methyl hexane.
LCMS-ESI (m/z) calculated for C.sub.44H.sub.56N.sub.4O.sub.5:
720.9; found 721.4 [M+H].sup.+, t.sub.R=5.39 min. (Method 16).
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-((5-methylhexyl)oxy)phenyl)--
pyrimidin-2-yl)phenyl)propanamido)propanoic acid (Compound 472)
##STR00244##
Prepared using General Procedure 8 from tert-butyl
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-((5-methylhexyl)oxy)phenyl)-
pyrimidin-2-yl)phenyl)propanamido)propanoate. LCMS-ESI (m/z)
calculated for C.sub.40H.sub.45N.sub.4O.sub.5: 664.9; found 664.8
[M+H].sup.+, t.sub.R=10.32 min. (Method 14).
Compound 473 was prepared from tert-butyl
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-y-
l)phenyl)propanamido)-propanoate using General Procedures 12 then
8.
tert-butyl
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(2-cyclohexyletho-
xy)-phenyl)-pyrimidin-2-yl)phenyl)propanamido)propanoate
##STR00245##
Prepared using General Procedure 12 from tert-butyl
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-y-
l)phenyl)propanamido)propanoate and (2-bromoethyl)cyclohexane.
LCMS-ESI (m/z) calculated for C.sub.45H.sub.56N.sub.4O.sub.5:
732.9; found 733.5 [M+H].sup.+, t.sub.R=5.59 min. (Method 16).
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(2-cyclohexylethoxy)phenyl)--
pyrimidin-2-yl)phenyl)propanamido)propanoic acid (Compound 474)
##STR00246##
Prepared using General Procedure 8 from tert-butyl
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(2-cyclohexylethoxy)phenyl)-
pyrimidin-2-yl)phenyl)propanamido)propanoate. LCMS-ESI (m/z)
calculated for C.sub.41H.sub.48N.sub.4O.sub.5: 676.9 found 677.4
[M+H].sup.+, t.sub.R=10.61 min. (Method 14).
Compounds 475 and 476 were prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) using General Procedures 7,
4, then 8.
4-benzyl
1-(tert-butyl)((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyl-
oxy)-phenyl)-pyrimidin-2-yl)phenyl)propanoyl)-L-aspartate
(INT-30)
##STR00247##
Prepared using General Procedure 7: To a stirred solution of
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) (594 mg, 1.00 mmol),
L-aspartic acid .beta.-benzyl ester .alpha.-tert-butyl ester
hydrochloride (398.4 mg, 1.20 mmol) in DMF (6 mL) was added DIEA
(554 .mu.l, 3.00 mmol). The mixture was cooled to 0.degree. C. and
HATU (418 mg, 1.10 mmol) in DMF (4 mL) was added over 5 mins. The
mixture was stirred at 0.degree. C. for 1 h. The reaction mixture
was added to water (200 mL) and the precipitate was filtered. The
precipitate was dissolved in DCM (20 mL), dried over MgSO.sub.4,
and concentrated. The crude product was purified by chromatography
0-100% EA in hexane to afford 751 mg (88%) of 4-benzyl
1-(tert-butyl)((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phen-
yl)pyrimidin-2-yl)phenyl)propanoyl)-L-aspartate (INT-30) as a white
solid. LCMS-ESI (m/z) calculated for
C.sub.52H.sub.62N.sub.4O.sub.7: 854.5; found 855.5 [M+H].sup.+,
t.sub.R=6.22 min (Method 16).
(S)-4-(tert-butoxy)-3-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptylo-
xy)-phenyl)-pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoic acid
(INT-31)
##STR00248##
Prepared using General Procedures 18: To 4-benzyl
1-(tert-butyl)((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phen-
yl)pyrimidin-2-yl)phenyl)propanoyl)-L-aspartate (INT-30) (50 mg,
0.058 mmol) in THF (2 mL) was added 10% Pd/C (10 mg). The reaction
vessel was flushed with hydrogen gas and the reaction was stirred
vigorously under hydrogen for 2 h at room temperature. The reaction
mixture was filtered to remove the catalyst and the solvent was
removed to give 38 mg (86%) of
(S)-4-(tert-butoxy)-3-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyl-
oxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoic acid
(INT-31) as a white solid. LCMS-ESI (m/z) calculated for
C.sub.45H.sub.56N.sub.4O.sub.7: 764.4; found 765.4 [M+H].sup.+,
t.sub.R=4.24 min (Method 16).
N.sup.2--((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyr-
imidin-2-yl)phenyl)propanoyl)-N.sup.4-methyl-L-asparagine (Compound
477)
##STR00249##
Prepared using General Procedure 7 and 8: To a stirred solution of
(S)-4-(tert-butoxy)-3-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyl-
oxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoic acid
(19 mg, 0.025 mmol), methylamine (40 wt % in water, 5.8 .mu.L,
0.075 mmol) in DMF (0.25 mL) was added DIEA (13.8 .mu.l, 0.075
mmol). The mixture was cooled to 0.degree. C. and HATU (19 mg, 0.05
mmol) was added. The mixture was stirred at room temperature for 18
h. The reaction mixture was added to water (2 mL) and the
precipitate was filtered. The precipitate was dissolved in DCM (2
mL), dried over MgSO.sub.4, and concentrated. The crude ester was
dissolved in DCM (1 mL) and TFA (0.2 mL) was added. The reaction
was stirred overnight. The solvent was removed and the crude
material was purified by preparative HPLC to afford 5 mg (25%) of
N.sup.2-((S)-2-(4-(tert-butyl)benamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyri-
midin-2-yl)phenyl)propanoyl)-N.sup.4-methyl-L-asparagine (Compound
477). LCMS-ESI (m/z) calculated for C.sub.42H.sub.51N.sub.5O.sub.6;
721.4; found 722.4 [M+H}.sup.+, t.sub.R=8.67 min (Method 14).
.sup.1H NMR (400 MHz, DMSO) .delta. 12.62 (s, 1H), 9.14 (s, 2H),
8.53 (d, J=8.5 Hz, 1H), 8.36 (d, J=7.9 Hz, 1H), 8.29 (d, J=8.2 Hz,
2H), 7.86 (d, J=4.6 Hz, 1H), 7.78 (d, J=8.7 Hz, 2H), 7.72 (d, J=8.3
Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.08 (d,
J=8.8 Hz, 2H), 4.89-4.73 (m, 1H), 4.66-4.53 (m, 1H), 4.03 (t, J=6.5
Hz, 3H), 3.26-3.18 (m, 1H), 3.11-3.00 (m, 1H), 2.64-2.53 (m, 5H),
1.80-1.67 (m, 2H), 1.51-1.38 (m, 2H), 1.38-1.21 (m, 15H), 0.87 (t,
J=6.8 Hz, 3H).
Compounds 478-487 were prepared from
(S)-4-(tert-butoxy)-3-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyl-
oxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoic acid
using General Procedures 7 and 8.
Compound 488 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) using General Procedures 7
and 4.
Compounds 489 and 490 were prepared from tert-butyl
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-y-
l)phenyl)propanamido)propanoate using General Procedures 12 then
8.
Compound 491 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) using General Procedures 7
then 4.
tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benza-
mido)-propanoyl)-D-alaninate (INT-32)
##STR00250##
To a stirring solution of
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propan-
oic acid (INT-27) (1.50 g, 3.10 mmol) in DMF (15 mL) were added
tert-butyl D-alaninate (680.0 mg, 3.73 mmol) and Et.sub.3N (802.3
mg, 6.2 mmol). The reaction was stirred for 1 hour at 0.degree. C.
and then HATU (877.5 mg, 3.37 mmol) in 2 mL DMF was added. The
reaction was stirred for 1 hour at 0.degree. C. and then warmed to
room temperature with stirring for 18 hours. The reaction solution
was extracted with aqueous NaHCO.sub.3 (3.times.20 mL). The
combined organics were dried over MgSO.sub.4 and evaporated. The
crude product was purified by column chromatography (50%) EA in
hexanes) to afford 1.44 g (76%) of tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)-prop-
anoyl)-D-alaninate (INT-32) as a solid powder. LCMS-ESI (m/z)
calculated for C.sub.31H.sub.37BrN.sub.4O.sub.4: 609.6; found 610.2
[M+H].sup.+, t.sub.R=4.05 min. (Method 16). .sup.1H NMR (400 MHz,
DMSO) .delta. 9.03 (s, 2H), 8.49 (d, J=8.7 Hz, 1H), 8.41 (d, J=7.2
Hz, 1H), 8.24 (d, J=8.2 Hz, 2H), 7.73 (t, J=7.4 Hz, 2H), 7.54-7.37
(m, 4H), 4.85 (td, J=10.1, 4.6 Hz, 1H), 4.16 (t, J=7.2 Hz, 1H),
3.24-2.97 (m, 2H), 1.50-1.29 (m, 9H), 1.32-1.17 (m, 12H).
(S)-2-(4-(3-((3-(tert-butoxy)-3-oxopropyl)amino)-2-(4-(tert-butyl)benzamid-
o)-3-oxopropyl)phenyl)pyrimidine-5-carboxylic acid (INT-33)
##STR00251##
Prepared using General Procedure 19. Oven-dried lithium formate
(136 mg, 2.6 mmol), DIEA (700 .mu.L, 3.9 mmol), and Ac.sub.2O (370
.mu.L, 3.9 mmol) were dissolved in anhydrous DMF (10 mL) in a
flame-dried flask under N.sub.2. After stirring for 30 min, the
solution was degassed via N.sub.2 bubbling. In a separate flask,
tert-butyl
(S)-3-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)pro-
panamido)propanoate (INT-28) (400 mg, 0.7 mmol, azeotropically
dried from THF) was dissolved in DMF (10 mL) and degassed via
N.sub.2 bubbling. Into the INT-28 solution was added
PdCl.sub.2(dppf) (48 mg, 0.07 mmol) and the resulting solution was
transferred via cannula into the lithium formate solution. The
flask was sealed and heated at 120.degree. C. for 4 h in a
microwave reactor. The reaction mixture was diluted with EA (250
mL) and washed with 10% citric acid (250 mL) and then washed with
H.sub.2O (250 mL) and purified by chromatography (EA/hexanes) to
afford 400 mg (99%) of
(S)-2-(4-(3-((3-(tert-butoxy)-3-oxopropyl)amino)-2-(4-(tert-butyl)benzami-
do)-3-oxopropyl)phenyl)pyrimidine-5-carboxylic acid (INT-33).
LCMS-ESI (m/z) calculated for C.sub.32H.sub.38N.sub.4O.sub.6:
574.7; found 575.3 [M+H].sup.+, t.sub.R=2.41 min. (Method 15).
methyl 2-(4-bromophenyl)-2-(4-(tert-butyl)benzamido)acetate
##STR00252##
Prepared using General Procedure 7. To a stirring solution of
methyl 2-amino-2-(4-bromophenyl)acetate (421 mg, 1.5 mmol),
4-(tert-butyl)benzoic acid (321 mg, 1.8 mmol), and DIEA (831 .mu.l,
4.5 mmol) in DMF (3 mL) cooled to 0.degree. C. was slowly added a
solution of HATU (380 mg, 1.65 mmol) in DMF (1.5 mL) in a drop-wise
fashion. The reaction mixture was allowed to warm slowly and
stirring continued for 4 h. The reaction mixture was poured onto
ice-water and the solid was filtered. The solid was dissolved in
DCM (10 mL), dried over MgSO.sub.4 and evaporated to afford 532 mg
(88%) of methyl
2-(4-bromophenyl)-2-(4-(tert-butyl)benzamido)acetate. LCMS-ESI
(m/z) calculated for C.sub.20H.sub.22BrNO.sub.3: 403.0; found 404.1
[M+H].sup.+, t.sub.R=3.61 min. (Method 16).
methyl
2-(4-(tert-butyl)benzamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl)acetate (INT-34)
##STR00253##
Prepared using General Procedure 10. A solution of methyl
2-(4-bromophenyl)-2-(4-(tert-butyl)benzamido)acetate (202 mg, 0.5
mmol), KOAc (147 mg, 1.5 mmol) and
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (165
mg, 0.65 mmol) in DMSO (3 mL) was de-gassed. PdCl.sub.2dppf (18 mg,
0.025 mmol) was added and the mixture was heated at 90.degree. C.
for 1.5 h. The crude reaction mixture was poured onto ice-water and
the solid was filtered. The solid was dissolved in DCM (5 mL),
dried over MgSO.sub.4, evaporated and purified by chromatography
(EA/hexane) to provide 71 mg (31%) of methyl
2-(4-(tert-butyl)benzamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl)acetate (INT-34). LCMS-ESI (m/z) calculated for
C.sub.26H.sub.34BNO.sub.5: 451.3; found 452.2 [M+H].sup.+,
t.sub.R=3.83 min (Method 16).
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2
carboxamido)-propanoic acid
##STR00254##
To a stirring solution of tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoate (INT-17) (15.7 g, 28.8 mmol) in DCM (30 mL) was
treated with TFA (30.0 g, 263.1 mmol). The reaction mixture was
stirred at room temperature for 18 hours to complete. The solvent
was evaporated and then co-evaporated with toluene (3.times.20 mL)
to remove trace TFA. The compound was dried under vacuum overnight
to afford 13.7 g (97%) of
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoic acid as powder. LCMS-ESI (m/z) calculated for
C.sub.22H.sub.22BrN.sub.3O.sub.3S: 487.1; found 488.1 [M+H].sup.+,
t.sub.R=2.55 min. (Method 16). .sup.1H NMR (400 MHz, DMSO) .delta.
9.05 (d, J=5.0 Hz, 2H), 8.64 (d, J=8.4 Hz, 1H), 8.25 (d, J=8.1 Hz,
2H), 7.62 (d, J=3.8 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 6.92 (d, J=3.8
Hz, 2H), 4.64 (td, J=10.5, 4.5 Hz, 1H), 3.26 (dd, J=13.8, 4.4 Hz,
1H), 3.11 (dd, J=13.7, 10.7 Hz, 1H), 1.32 (s, 9H).
methyl
(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thi-
ophene-2-carboxamido)propanoyl)pyrrolidine-3-carboxylate
(INT-35)
##STR00255##
To a stirring solution of methyl (S)-pyrrolidine-3-carboxylate
(357.0 mg, 2.16 mmol) in DMF (10 mL) were added DIEA (465.26 mg,
3.60 mmol) and
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoic acid (700.0 mg, 1.44 mmol). The solution was
cooled to 0.degree. C. at ice bath and then HATU (677.55 mg, 2.88
mmol) in 2 mL DMF solution was slowly added. The reaction was
stirred 1 hour at 0.degree. C. and then warmed to RT with stirring
for 2 hours. The reaction solution was extracted with DCM
(3.times.20 mL) and aqueous NaHCO.sub.3 (3.times.10 mL). The
combined organics were dried over MgSO.sub.4 and evaporated. The
final compound was purified by column chromatography (40% DCM in
hexane) to afford 501.0 mg (58%) of methyl
(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-
-2-carboxamido)propanoyl)pyrrolidine-3-carboxylate (INT-35) as a
powder. LCMS-ESI (m/z calculated for
C.sub.28H.sub.31BrN.sub.4O.sub.4S: 598.1; found 599.3 [M+H].sup.+,
t.sub.R=3.553 min. (Method 16). .sup.1H NMR (400 MHz, DMSO) .delta.
9.05 (d, J=1.1 Hz, 2H), 8.77 (dd, J=11.5, 8.3 Hz, 1H), 8.25 (d,
J=7.7 Hz, 2H), 7.72 (d, J=3.5 Hz, 1H), 7.46 (d, J=8.3 Hz, 2H), 6.92
(d, J=3.8 Hz, 1H), 4.98-4.73 (m, 1H), 3.88 (dd, J=10.3, 8.0 Hz,
1H), 3.71 (dd, J=15.5, 7.5 Hz, 1H), 3.50 (ddd, J=18.3, 12.2, 5.4
Hz, 2H), 3.38 (dd, J=17.3, 7.6 Hz, 1H), 3.23 (ddd, J=28.0, 15.0,
8.7 Hz, 1H), 3.18-2.85 (m, 3H), 2.17-1.96 (m, 2H), 1.87 (td,
J=15.2, 7.4 Hz, 1H), 1.32 (s, 9H).
tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiop-
hene-2-carboxamido)propanoyl)-D-alaninate
##STR00256##
To a stirring solution of tert-butyl D-alaninate (5.60 g, 30.80
mmol) in DMF (50 mL) were added DIEA (8.29 g, 64.18 mmol) and
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoic acid (12.5 g, 25.67 mmol). The solution was
cooled to 0.degree. C. at ice bath and then HATU (9.06 g, 38.50
mmol) in 15 mL DMF solution was slowly added. The reaction was
stirred 1 hour at 0.degree. C. and then warmed to RT with stirring
for 2 hours. The reaction solution was extracted with DCM
(3.times.50 mL) and aqueous NaHCO.sub.3 (3.times.30 mL). The
combined organics were dried over MgSO.sub.4 and evaporated. The
final compound was purified by column chromatography (40% DCM in
hexane) to afford 14.7 g (94%) of tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alaninate as solid powder. LCMS-ESI (m/z)
calculated for C.sub.29H.sub.35BrN.sub.4O.sub.4S: 614.2; found
615.3 [M+H].sup.+, t.sub.R=3.914 min. (Method 16). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.83 (d, J=3.6 Hz, 2H), 8.36 (d, J=8.2 Hz,
2H), 7.39 (d, J=8.2 Hz, 2H), 7.34 (d, J=3.8 Hz, 1H), 6.81 (d, J=3.8
Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 6.34 (d, J=7.2 Hz, 1H), 4.88 (d,
J=5.9 Hz, 1H), 4.41 (t, J=7.2 Hz, 1H), 3.31 (dd, J=13.6, 5.8 Hz,
1H), 3.20 (dd, J=13.6, 7.8 Hz, 1H), 1.51-1.32 (m, 18H), 1.27 (d,
J=7.1 Hz, 3H). .sup.13C NMR (101 MHz, DMSO) .delta. 172.02, 171.31,
162.28, 162.13, 161.42, 158.55, 142.27, 136.34, 134.66, 130.20,
128.82, 127.92, 123.07, 118.63, 80.90, 54.45, 48.86, 39.59, 39.38,
32.39, 28.04, 17.68.
tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydro-
xyphenyl)-pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate (INT-36)
##STR00257##
To a 100 ml flask were added (4-hydroxyphenyl)boronic acid (224.6
mg, 1.6 mmol), sodium carbonate decahydrate (96.0 mg, 1.6 mmol),
tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alaninate (500.0 mg, 1.6 mmol),
Pd(dppf)Cl.sub.2 (58.5 mg, 0.08 mmol), THF (2.0 mL), CH.sub.3CN
(2.0 ml) and water (1.0 mL). The solution was degassed using
N.sub.2 bubbling for 10 min. The reaction mixture was heated to
80.degree. C. for 2 hours. The reaction mixture was dried under
reduced pressure to remove the solvent and diluted in DCM (20 mL).
The mixture was extracted with DCM (3.times.20 mL) and aqueous
NaHCO.sub.3 (3.times.10 mL). The combined organics were dried over
MgSO.sub.4 and evaporated. The final compound was purified by
column chromatography (40% DCM in hexane) to afford 462.3 mg (91%)
of tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)p-
yrimidin-2-yl)phenyl)propanoyl)-D-alaninate (INT-36) as a solid.
LCMS-ESI (m/z) calculated for C.sub.35H.sub.40N.sub.4O.sub.5S:
628.3; found 629.3 [M+H].sup.+, t.sub.R=3.447 min. (Method 16).
.sup.1H NMR (400 MHz, DMSO) .delta. 9.79 (s, 1H), 9.12 (s, 2H),
8.55 (t, J=16.2 Hz, 1H), 8.43 (d, J=7.2 Hz, 1H), 8.30 (d, J=8.1 Hz,
2H), 7.69 (t, J=7.5 Hz, 3H), 7.50 (dd, J=15.4, 8.3 Hz, 2H),
7.00-6.85 (m, 2H), 6.75 (t, J=9.9 Hz, 1H), 4.80 (td, J=9.7, 4.7 Hz,
1H), 4.15 (p, J=7.2 Hz, 1H), 3.10 (ddd, J=39.3, 19.4, 11.8 Hz, 2H),
1.40 (d, J=6.6 Hz, 9H), 1.31 (s, 9H), 1.23 (t, J=11.1 Hz, 3H).
methyl
(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hyd-
roxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate
(INT-37)
##STR00258##
To a 10 ml flask were added (4-hydroxyphenyl)boronic acid (60.7 mg,
0.44 mmol), sodium carbonate decahydrate (26.4 mg, 0.44 mmol),
methyl
(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-
-2-carboxamido)propanoyl)pyrrolidine-3-carboxylate (INT-35) (130.0
mg, 0.44 mmol), Pd(dppf)Cl.sub.2 (16.09 mg, 0.022 mmol), THF (2.0
mL), CH.sub.3CN (2.0 ml) and water (1.0 mL). The solution was
degassed using N.sub.2 bubbling for 10 min. The reaction mixture
was heated to 80.degree. C. for 2 hours. The reaction mixture was
dried under reduced pressure to remove the solvent and diluted in
DCM (20 mL). The mixture was extracted with DCM (3.times.10 mL) and
aqueous NaHCO.sub.3 (3.times.10 mL). The combined organics were
dried over MgSO.sub.4 and evaporated. The final compound was
purified by column chromatography (50% DCM in hexane) to afford
102.0 mg (76%) of methyl
(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyph-
enyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate
(INT-37) as a solid powder. LCMS-ESI (m/z) calculated for
C.sub.34H.sub.36N.sub.4O.sub.5S: 612.3; found 613.3 [M+H].sup.+,
t.sub.R=3.138 min. (Method 16). .sup.1H NMR (400 MHz, DMSO) .delta.
9.81 (s, 1H), 9.13 (d, J=1.5 Hz, 2H), 8.77 (dd, J=11.4, 8.1 Hz,
1H), 8.31 (d, J=8.2 Hz, 2H), 7.73 (d, J=3.8 Hz, 1H), 7.69 (d, J=8.4
Hz, 2H), 7.46 (d, J=8.3 Hz, 2H), 6.99-6.84 (m, 3H), 4.88 (s, 1H),
3.72 (d, J=8.9 Hz, 1H), 3.62 (s, 1H), 3.59 (d, J=6.4 Hz, 1H), 3.50
(ddd, J=18.7, 12.0, 5.8 Hz, 1H), 3.36 (d, J=7.5 Hz, 1H), 3.27-3.16
(m, 1H), 3.18-2.97 (m, 3H), 2.15-1.95 (m, 2H), 1.88 (dd, J=12.5,
7.5 Hz, 1H), 1.32 (s, 9H).
tert-butyl
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thi-
ophene-2-carboxamido)propanoyl)azetidine-3-carboxylate (INT-38)
##STR00259##
To a stirring solution of tert-butyl azetidine-3-carboxylate (64.55
mg, 0.41 mmol) in DMF (1 mL) were added DIEA (169.6 mg, 1.31 mmol),
and
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoic acid (100.0 mg, 0.21 mmol). The solution was
cooled to 0.degree. C. at ice bath and then HATU (74.11 mg, 1.31
mmol) in 1 mL DMF solution was slowly added. The reaction was
stirred 1 hour at 0.degree. C. and then warmed to RT with stirring
for 2 hours. The reaction solution was extracted with DCM
(3.times.10 mL) and aqueous NaHCO.sub.3 (3.times.10 mL). The
combined organics were dried over MgSO.sub.4 and evaporated to
afford 117.6 mg (85%) of tert-butyl
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylate (INT-38) as a solid
powder without further purification for next step. LCMS-ESI (m/z)
calculated for C.sub.30H.sub.35BrN.sub.4O.sub.4S: 626.2; found
627.2 [M+H].sup.+, t.sub.R=3.884 min. (Method 16).
methyl
(S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phe-
nyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate
##STR00260##
Prepared using General Procedure 7. To a stirring solution of
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)propanoic acid (INT-22) (2082 mg, 2.75 mmol), methyl
(S)-pyrrolidine-3-carboxlate HCl (545 mg, 3.30 mmol), and DIEA
(1523 .mu.l, 8.25 mmol) in DMF (6 mL) cooled to 0.degree. C. was
slowly added a solution of HATU (1254 mg, 3.30 mmol) in DMF (5 mL)
in a drop-wise fashion. The reaction mixture was allowed to warm
slowly and stirring continued for 4 h. The reaction mixture was
poured onto ice-water and the solid was filtered. The solid was
dissolved in EA (50 mL), dried over MgSO.sub.4, evaporated and
purified by chromatography (EA/hexane) to provide 932 mg (52%) of
methyl
(S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)py-
rimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate. LCMS-ESI
(m/z) calculated for C.sub.40H.sub.46N.sub.4O.sub.6: 678.3; found
679.3 [M+H].sup.+, t.sub.R=4.50 min (Method 16).
methyl
(S)-1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phen-
yl)propanoyl)pyrrolidine-3-carboxylate (INT-39)
##STR00261##
Prepared using General Procedure 18: To a stirred solution of
methyl
(S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)py-
rimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate (962 mg,
1.42 mmol) in MeOH (10 mL) was added palladium on carbon (10 wt %,
150 mg). The reaction mixture was flushed with hydrogen and stirred
under hydrogen at room temperature for 1.5 h. The reaction mixture
was filtered through Celite and concentrated to give 752 mg (97%)
of methyl
(S)-1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)pro-
panoyl)pyrrolidine-3-carboxylate (INT-39). LCMS-ESI (m/z)
calculated for C.sub.32H.sub.40N.sub.4O.sub.4: 544.3; found 545.3
[M+H].sup.+, t.sub.R=3.61 min (Method 16).
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)prop-
anoic acid
##STR00262##
Prepared using General Procedure 8: To a stirred solution of
(S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propano-
ate (INT-7) (1.08 g, 2.11 mmol) in DCM (10 mL) was added TFA (5
mL). After 16 h, the mixture was diluted with toluene (10 mL) and
evaporated. Further toluene (2.times.10 mL) was evaporated from the
residue to afford 962 mg (100%) of
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)pro-
panoic acid as an off-white solid. LCMS-ESI (m/z) calculated for
C.sub.21H.sub.18BrN.sub.3O.sub.4: 455.1; found 456.0 [M+H].sup.+,
t.sub.R=5.81 min (Method 10).
tert-butyl
((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl-
)phenyl)propanoyl)-D-alaninate (INT-42)
##STR00263##
Prepared using General Procedure 7: To a stirred solution of
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)pro-
panoic acid (962 mg, 2.11 mmol) and (R)-tert-butyl
2-aminopropanoate hydrochloride (383 mg, 2.11 mmol) in DMF (20 mL)
was added DIEA (1.2 mL, 6.32 mmol). The mixture was cooled to
0.degree. C. and HATU (802 mg, 2.11 mmol) was added portionwise.
The cooling bath was removed and the mixture was allowed to warm to
room temperature. After 1 h, the mixture was poured onto citric
acid (100 mL of a 0.1 M aqueous solution) and iso-hexanes (20 mL)
and the resulting precipitate collected by filtration, washing
successively with water (2.times.10 mL), ACN (3 mL) and iso-hexanes
(2.times.5 mL) to afford 1.1 g (89%) of tert-butyl
((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)pr-
opanoyl)-D-alaninate (INT-42) as a white solid. LCMS-ESI (m/z)
calculated for C.sub.28H.sub.31BrN.sub.4O.sub.5: 582.2; found 605.2
[M+Na].sup.+, t.sub.R=7.94 min (Method 10).
2-amino-2-(2,5-dimethyloxazol-4-yl)acetic acid hydrochloride
##STR00264##
To a stirred solution of 2,5-dimethyloxazole-4-carbaldehyde (272
mg, 2.17 mmol) and ammonium carbonate (564 mg, 5.87 mmol) in EtOH
(6 mL) and water (2 mL) at 50.degree. C. was added dropwise over 20
minutes a solution of potassium cyanide (177 mg, 2.72 mmol) in
water (3.8 mL). The solution was stirred at 60.degree. C. for 16 h.
The EtOH was distilled off at 80.degree. C. and HCl added (0.2 mL
of a 37% aqueous solution). The mixture was allowed to cool to room
temperature and the precipitate collected by filtration, washing
successively with water (5 mL) and iso-hexanes (2.times.5 mL). This
was dissolved in MeOH (14 mL) with stirring and treated with
potassium hydroxide (5.2 mL of a 2.5 M aqueous solution, 13.1 mmol)
and the solution stirred at 60.degree. C. for 100 h. The mixture
was allowed to cool and acidified with HCl. Solvents were
evaporated and the residue treated with MeOH (10 mL). The mixture
was filtered and the filtrate evaporated to afford 205 mg (55%) of
2-amino-2-(2,5-dimethyloxazol-4-yl)acetic acid hydrochloride as an
orange oil. LCMS-ESI (m/z) calculated for
C.sub.7H.sub.10N.sub.2O.sub.3: 170.1; found 171.1 [M+H].sup.+,
t.sub.R=0.23 min (Method 11). .sup.1H NMR (400 MHz, DMSO) .delta.
8.71 (br s, 3H), 5.13 (s, 1H), 2.38 (s, 3H), 2.34 (s, 3H).
methyl 2-amino-2-(2,5-dimethyloxazol-4-yl)acetate hydrochloride
(INT-43)
##STR00265##
Prepared using General Procedure 22: To a stirred solution of
2-amino-2-(2,5-dimethyloxazol-4-yl)acetic acid hydrochloride (150
mg, 0.726 mmol) in MeOH (5 mL) was added HCl (1.2 mL of a 37%
aqueous solution, 14.5 mmol) and the mixture heated under reflux
for 4 h. The mixture was allowed to cool and solvents evaporated.
The residue was treated with MeOH (12 mL) and filtered. The
filtrate was evaporated to afford 135 mg (84%) of methyl
2-amino-2-(2,5-dimethyloxazol-4-yl)acetate hydrochloride (INT-43).
LCMS-ESI (m/z) calculated for C.sub.8H.sub.12N.sub.2O.sub.3: 184.1;
found 185.1 [M+H].sup.+, t.sub.R=0.23 min (Method 11). .sup.1H NMR
(400 MHz, DMSO) .delta. 8.94 (br s, 3H), 5.35 (s, 1H), 3.73 (s,
3H), 2.38 (s, 3H), 2.36 (s, 3H).
4-benzyl
1-(tert-butyl)((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-
-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-aspartate
(INT-47)
##STR00266##
Prepared using General Procedure 7: To a stirred solution of
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) (600 mg, 1.00
mmol), L-aspartic acid .beta.-benzyl ester .alpha.-tert-butyl ester
hydrochloride (398.4 mg, 1.20 mmol) in DMF (6 mL) was added DIEA
(554 .mu.l, 3.00 mmol). The mixture was cooled to 0.degree. C. and
HATU (418 mg, 1.10 mmol) in DMF (4 mL) was added over 5 mins. The
mixture was stirred at 0.degree. C. for 0.5 h. The reaction mixture
was added to water (250 mL) and the precipitate was filtered. The
precipitate was dissolved in DCM (20 mL), dried over MgSO.sub.4,
and concentrated. The crude product was purified by chromatography
0-100% EA in hexane to afford 789 mg (92%) of 4-benzyl
1-(tert-butyl)((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(-
heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-aspartate
(INT-47) as a white solid. LCMS-ESI (m/z) calculated for
C.sub.50H.sub.60N.sub.4O.sub.7S: 860.4; found 861.4 [M+H].sup.+,
t.sub.R=6.028 min (Method 16).
(S)-4-(tert-butoxy)-3-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4--
(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoic
acid (INT-44)
##STR00267##
Prepared using General Procedures 18: To 4-benzyl
1-(tert-butyl)((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(-
heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-aspartate
(INT-47) (345 mg, 0.4 mmol) in THF (5 mL) was added 10% Pd/C (60
mg). The reaction vessel was flushed with hydrogen gas and the
reaction was stirred vigorously under hydrogen overnight at room
temperature. The reaction mixture was filtered to remove the
catalyst, the solvent was removed, and the crude product was
purified by chromatography 0-100% EA in hexane to afford 228 mg
(66%) of
(S)-4-(tert-butoxy)-3-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-
-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoic
acid (INT-44) as a white solid. LCMS-ESI (m/z) calculated for
C.sub.43H.sub.54N.sub.4O.sub.7S: 770.4; found 771.3 [M+H].sup.+,
t.sub.R=4.21 min (Method 16).
tert-butyl
((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrim-
idin-2-yl)phenyl)propanoyl)-D-alaninate (INT-45)
##STR00268##
To a 10 ml flask were added (4-hydroxyphenyl)boronic acid (317.23
mg, 2.30 mmol), sodium carbonate decahydrate (138.0 mg, 2.3 mmol),
tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)-prop-
anoyl)-D-alaninate (INT-32) (700.0 mg, 1.15 mmol), Pd(dppf)Cl.sub.2
(87.8 mg, 0.12 mmol), THF (10 mL), CH.sub.3CN (10 ml) and water (5
mL). The solution was degassed using N.sub.2 bubbling for 10 min.
The reaction mixture was heated to 80.degree. C. for 2 hours. The
mixture was extracted with DCM (3.times.20 mL) and aqueous
NaHCO.sub.3 (3.times.10 mL). The combined organics were dried over
MgSO.sub.4 and evaporated. The final compound was purified by
column chromatography (40% DCM in hexane) to afford 595.0 mg (83%)
of tert-butyl
((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)-
phenyl)propanoyl)-D-alaninate (INT-45) as solid. LCMS-ESI (m/z)
calculated for C.sub.37H.sub.42N.sub.4O.sub.5: 622.3; found 623.3
[M+H].sup.+, t.sub.R=3.635 min. (Method 16). .sup.1H NMR (400 MHz,
DMSO) .delta. 9.79 (s, 1H), 9.11 (s, 2H), 8.50 (d, J=8.7 Hz, 1H),
8.41 (d, J=7.2 Hz, 1H), 8.30 (d, J=8.2 Hz, 2H), 7.75 (d, J=8.4 Hz,
2H), 7.68 (d, J=8.6 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.4
Hz, 2H), 6.92 (d, J=8.6 Hz, 2H), 4.85 (td, J=9.9, 4.6 Hz, 1H), 4.17
(p, J=7.1 Hz, 1H), 3.24-3.00 (m, 2H), 1.46-1.34 (m, 9H), 1.32-1.19
(m, 12H).
tert-butyl
N.sup.2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N.sup.4-methyl-D-a-
sparaginate
##STR00269##
Prepared using General Procedures 7: To
(R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobu-
tanoic acid (205.7 mg, 0.5 mmol) in DMF (5 mL) at 0.degree. C. was
added HATU (380 mg, 1.0 mmol). After stirring for 3 min, DIEA (277
.mu.L, 1.5 mmol) and methylamine (40 wt % in water, 116 .mu.L, 1.5
mmol) were added. The reaction mixture was stirred at room
temperature for 1 h. The reaction mixture was added to water (75
mL) and the precipitate was filtered and dried to give 201 mg (95%)
of tert-butyl
N.sup.2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N.sup.4-methyl-D-asparaginat-
e as a colorless semi-solid. LCMS-ESI (m/z) calculated for
C.sub.24H.sub.28N.sub.2O.sub.5: 424.2; found 425.2 [M+H].sup.+,
t.sub.R=3.22 min (Method 16).
tert-butyl N.sup.4-methyl-D-asparaginate (INT-46)
##STR00270##
To tert-butyl
N.sup.2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N.sup.4-methyl-D-asparaginat-
e (200 mg, 0.47 mmol) in DCM (0.93 mL) was added piperidine (233
.mu.L, 2.35 mmol). The reaction mixture was stirred at room
temperature for 1 h. All solvent was removed to give 215 mg of
tert-butyl N.sup.4-methyl-D-asparaginate (INT-46) as a mixture with
1-((9H-fluoren-9-yl)methyl)piperidine. The mixture was used without
purification in the next reaction. LCMS-ESI (m/z) calculated for
C.sub.9H.sub.18N.sub.2O.sub.3: 202.1; found 203.1 [M+H].sup.+,
t.sub.R=0.534 min (Method 16).
tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hyd-
roxyphenyl)-pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
(INT-48)
##STR00271##
Prepared using General Procedure 10. Into a solution of tert-butyl
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylate (INT-38) (60 mg, 0.1
mmol) in dioxane (2 mL) and H.sub.2O (1 mL) were added sodium
carbonate, decahydrate (60 mg, 0.2 mmol), 4-hydroxyphenylboronic
acid (17 mg, 0.1 mmol) and PdCl.sub.2(dppf) (7 mg, 0.01 mmol). The
mixture was heated at 80.degree. C. for 2.5 h then cooled to room
temp, diluted with H.sub.2O (100 mL) and extracted into EA
(2.times.100 mL). The resulting organic layers were combined, dried
(Na.sub.2SO.sub.4) and concentrated to yield 75 mg (117%) of crude
tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl-
)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (INT-48)
which was used without further purification. LCMS-ESI (m/z)
calculated for C.sub.36H.sub.40N.sub.4O.sub.5S: 640.8; found
341.3[M+H].sup.+, t.sub.R=3.42 min. (Method 15).
Compound 492 was prepared from
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)propanoic acid (INT-22) and (S)-methyl
2-amino-6-((tert-butoxycarbonyl)amino)hexanoate hydrochloride using
General Procedures 7, 18, 7, 4 and 8 sequentially.
Compounds 493, 494 and 500 were prepared from
(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptylox-
y)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylic
acid (Compound 328) using General Procedures 7 and 4
sequentially.
Compounds 495 and 496 were prepared
from(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(hept-
yloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-2-carboxylic
acid (Compound 328) using General Procedure 7.
Compound 497 was prepared
from(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(hept-
yloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-pyrrolidine-2-carboxylic
acid (Compound 328) using General Procedures 7 and 8
sequentially.
Compounds 498 and 499 were prepared from
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)propanoic acid (INT-22) using General Procedures 7,
18, 7 and 8 sequentially.
Compounds 501, 592-602, 604, 607-621, 625-629, 631, 633, 634,
636-641, 644, 655, 668 and 669 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 7 then 4.
Compound 502 was prepared from 4-benzyl
1-(tert-butyl)((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phen-
yl)pyrimidin-2-yl)phenyl)propanoyl)-L-aspartate (INT-30) using
General Procedure 8.
Compounds 503-507, 579, and 580 were prepared from
(S)-4-(benzyloxy)-2-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptylox-
y)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoic acid
(Compound 502) using General Procedures 7 then 18.
Compounds 508-511 were prepared from
(S)-4-(tert-butoxy)-3-((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyl-
oxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoic acid
(INT-31) using General Procedures 7 then 8.
Compounds 512-523 were prepared from
(S)-4-(tert-butoxy)-3-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-
-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoic
acid (INT-44) using General Procedures 7 then 8.
Compound 524 was prepared from 4-benzyl
1-(tert-butyl)((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(-
heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-aspartate
(INT-47) using General Procedure 8.
Compounds 525-533 were prepared from
(S)-4-(benzyloxy)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(-
5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoic
acid (Compound 524) using General Procedures 7 then 18.
Compound 534 was prepared from
(S)-4-(benzyloxy)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(-
5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-4-oxobutanoic
acid (Compound 524) using General Procedures 7, 18, then 8.
Compound 535 was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 3 then 8.
Compound 536 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) and
2-amino-2-(2,5-dimethyloxazol-4-yl)acetic acid hydrochloride
(INT-43) using General Procedures 7 and 4 sequentially.
Compounds 537 and 554 were prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) using General Procedures 7
then 8.
Compounds 538-553, 555-578, 583-588, 622-624, 632 and 660-662 were
prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) using General Procedures 7
then 4.
Compound 581 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) using General Procedures 7,
4 then 18.
Compound 582 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) using General Procedures 7,
8 then 4.
tert-butyl
(R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(methylamin-
o)-4-oxobutanoate
##STR00272##
Prepared using General Procedure 7. To a stirring solution of
(R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobu-
tanoic acid (308 mg, 0.75 mmol), methylamine (40 wt % in water, 174
.mu.L, 2.25 mmol), and DIEA (415 .mu.L, 2.25 mmol) in DMF (7.5 mL)
cooled to 0.degree. C. was added HATU (569 mg, 1.5 mmol). The
reaction mixture was allowed to warm slowly and stirring continued
for 18 h. The reaction mixture was poured onto ice-water and the
solid was filtered. The solid was dissolved in DCM (10 mL), dried
over MgSO.sub.4 and evaporated. The crude product was purified by
column chromatography to afford 226 mg (71%) of tert-butyl
(R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(methylamino)-4-oxobu-
tanoate. LCMS-ESI (m/z) calculated for
C.sub.24H.sub.28N.sub.2O.sub.5: 424.2; found 447.1 [M+Na].sup.+,
t.sub.R=3.12 min. (Method 16).
tert-butyl (R)-3-amino-4-(methylamino)-4-oxobutanoate
##STR00273##
To a stirring solution of tert-butyl
(R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(methylamino)-4-oxobu-
tanoate (226 mg, 0.53 mmol), in DCM (1.05 mL) was added piperidine
(263 .mu.L, 2.7 mmol). The reaction mixture was stirred for 1 h at
room temperature. The solvent was evaporated to afford 250 mg
(100%) of tert-butyl (R)-3-amino-4-(methylamino)-4-oxobutanoate as
a mixture with 1-((9H-fluoren-9-yl)methyl)piperidine. The mixture
was used without purification in the next reaction. LCMS-ESI (m/z)
calculated for C.sub.9H.sub.18N.sub.2O.sub.3: 202.1; found 225.1
[M+Na].sup.+, t.sub.R=0.50 min. (Method 15).
Compound 589 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) and tert-butyl
(R)-3-amino-4-(methylamino)-4-oxobutanoate using General Procedures
7 then 8.
tert-butyl
(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phe-
nyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
##STR00274##
Prepared using General Procedure 7: A stirred solution of
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)propanoic acid (INT-22) (1 g, 1.76 mmol), tert-butyl
azetidine-3-carboxylate (0.554 g, 1.76 mmol) and DIEA (1.30 mL,
7.05 mmol) in DMF (20 mL) at 0.degree. C. was treated with HATU
(0.703 g, 1.85 mmol), added portionwise. After 10 min, the cooling
bath was removed. After a further 1 h the mixture was poured onto
0.2 M HCl (100 mL) and extracted with EA (3.times.30 mL). The
combined organic extracts were washed with brine (20 mL), dried
over MgSO.sub.4 and evaporated. Column chromatography
(EA/DCM/iso-hexanes) gave 708 mg (58%) of tert-butyl
(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimi-
din-2-yl)phenyl)propanoyl)azetidine-3-carboxylate as an off-white
solid. LCMS-ESI (m/z) calculated for
C.sub.42H.sub.50N.sub.4O.sub.6: 706.4; found 707.1 [M+H].sup.+,
t.sub.R=3.60 min (Method 6).
tert-butyl
(S)-1-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl-
)-pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
##STR00275##
Prepared using General Procedures 18 and 7: To a stirred solution
of (S)-tert-butyl
1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin--
2-yl)phenyl)propanoyl)azetidine-3-carboxylate (708 mg, 1.00 mmol)
and triethylsilane (352 .mu.L, 2.20 mmol) in DCM (10 mL) was added
a solution of diacetoxypalladium (22.5 mg, 0.100 mmol) and
triethylamine (43 .mu.L, 0.30 mmol) in DCM (2 mL). After 16 h, the
mixture was filtered through Celite and solvents evaporated. The
residue was taken up in DMF (6 mL) and the resulting solution added
to a stirred solution of active ester prepared by the action of
HATU (399 mg, 1.05 mmol) and DIEA (0.55 mL, 3.00 mmol) on
4-(tert-butyl)benzoic acid (196 mg, 1.10 mmol) in DMF (5 mL) over
10 min. After 1 h, the mixture was poured onto 0.5 M HCl (100 mL)
and extracted with EA (3.times.50 mL). The combined organic
extracts were washed with brine (20 mL), dried over MgSO.sub.4 and
evaporated. Column chromatography (EA/DCM/iso-hexanes) gave 583 mg
(80%) of tert-butyl
(S)-1-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)propanoyl)azetidine-3-carboxylate. LCMS-ESI (m/z)
calculated for C.sub.45H.sub.56N.sub.4O.sub.5: 732.4; no m/z
observed, t.sub.R=3.99 min (Method 11).
(S)-1-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin--
2-yl)phenyl)propanoyl)azetidine-3-carboxylic acid (Compound
590)
##STR00276##
Prepared using General Procedure 8: To a stirred solution of
(S)-tert-butyl
1-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-y-
l)phenyl)propanoyl)azetidine-3-carboxylate (580 mg, 0.791 mmol) in
DCM (6 mL) was added TFA (2 mL). After 3 h, the mixture was diluted
with toluene (20 mL) and the solvents evaporated. Column
chromatography (acetic acid/EA/DCM/iso-hexanes) gave moderately
pure product. This was further purified by re-slurry from DCM/ACN
then iso-propyl acetate. The resulting solid was again purified by
column chromatography (acetic acid/EA/DCM/iso-hexanes) then
reslurried from diethyl ether to afford 212 mg (40%) of
(S)-1-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)-propanoyl)azetidine-3-carboxylic acid (Compound 590).
LCMS-ESI (m/z) calculated for C.sub.41H.sub.48N.sub.4O.sub.5;
676.4; no m/z observed, t.sub.R=10.23 min (Method 10). The chiral
purity was >95% e.e (chiral Method). .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 12.80 (s, 1H), 9.16 (d, J=1.5 Hz, 2H), 8.75 (dd,
J=8.1, 3.7 Hz, 1H), 8.36-8.31 (m, 2H), 7.85-7.75 (m, 4H), 7.49-7.46
(m, 4H), 7.11-7.05 (m, 2H), 4.74-4.68 (m, 1H), 4.45 (t, J=8 Hz,
0.5H), 4.33-4.30 (m, 0.5H), 4.24-4.16 (m, 1H), 4.06-4.00 (m, 3H),
3.47-3.40 (m, 1H), 3.90 (ddd, J=13.5, 9.7, 6.0 Hz, 1H), 3.18-3.05
(m, 2H), 1.77-1.70 (m, 2H), 1.46-1.24 (m, 17H), 0.89-0.86 (m,
3H).
Compound 591 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) and tert-butyl
N.sup.4-methyl-D-asparaginate (INT-46) using General Procedures 7
then 8.
Compounds 603, 605, 645-648, 652, 653, 656-659 and 664 were
prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 7 then 8.
Compound 606 was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 7, 4 then 8.
Compound 630 was was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) and
tert-butyl (R)-3-amino-4-(methylamino)-4-oxobutanoate using General
Procedures 7 then 8.
(S)-methyl
1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)-
-pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
##STR00277##
Prepared using General Procedure 7: To a stirred solution of
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)-propanoic acid (INT-22) (2.2 g, 3.88 mmol) and methyl
azetidine-3-carboxylate, HCl (0.705 g, 4.65 mmol) in DMF (25 mL)
was added DIEA (2.7 mL, 15.5 mmol) and the mixture cooled to
0.degree. C. HATU (1.621 g, 4.26 mmol) was added portion-wise over
10 minutes. After 3 h, further methyl azetidine-3-carboxylate, HCl
(0.223 g, 1.938 mmol) and HATU (0.456 g, 1.938 mmol) were added.
The mixture was allowed to stir at room temperature for 100 h. The
mixture was treated with citric acid (50 mL of a 0.1 M aqueous
solution) and water (20 mL) and extracted with EA (2.times.100 mL).
The combined organic extracts were washed with brine (80 mL), dried
over MgSO.sub.4 and solvents evaporated. Column chromatography
(EA/iso-hexanes) gave 1.45 g (56%) of (S)-methyl
1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin--
2-yl)phenyl)propanoyl)azetidine-3-carboxylate as a colourless
glass. LCMS-ESI (m/z) calculated for
C.sub.39H.sub.44N.sub.4O.sub.6: 664.3; found 665.3 [M+H].sup.+,
t.sub.R=3.37 min (Method 6).
(S)-methyl
1-(2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)p-
ropanoyl)-azetidine-3-carboxylate
##STR00278##
Prepared using General Procedure 18: A solution of (S)-methyl
1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin--
2-yl)phenyl)-propanoyl)azetidine-3-carboxylate (1.2 g, 1.81 mmol)
in MeOH (150 mL) was passed over a 10% Pd/C CatCart (55.times.4 mm)
at 65.degree. C. in a Thales Nanotechnology H-Cube reactor at 2.1
mL/min. The solvent was evaporated and the residue purified by
column chromatography (Ammonia/MeOH/DCM) to afford 604 mg (63%) of
(S)-methyl
1-(2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)a-
zetidine-3-carboxylate. LCMS-ESI (m/z) calculated for
C.sub.31H.sub.38N.sub.4O.sub.4: 530.3; found 531.0 [M+H].sup.+,
t.sub.R=1.60 min (Method 6).
methyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyl-
oxy)phenyl)-pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
##STR00279##
To a stirred solution of (S)-methyl
1-(2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)a-
zetidine-3-carboxylate (360 mg, 0.678 mmol) and
5-(tert-butyl)thiophene-2-carboxylic acid (125 mg, 0.678 mmol) in
DMF (6 mL, 77 mmol) was added DIEA (0.47 mL, 2.71 mmol) and the
mixture cooled to 0.degree. C. HATU (284 mg, 0.746 mmol) was added
portion-wise and the reaction stirred at room temperature for 1 h.
The mixture was poured onto citric acid (70 mL of a 10% w/w aqueous
solution) and extracted with EA (2.times.100 mL). The combined
organic extracts were washed with brine (50 mL), dried over
MgSO.sub.4 and solvents evaporated. Column chromatography
(EA/iso-hexanes) gave 389 mg (82%) of (S)-methyl
1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl-
)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate as a pale
yellow solid. LCMS-ESI (m/z) calculated for
C.sub.40H.sub.48N.sub.4O.sub.5S: 696.3; found 697.0 [M+H].sup.+,
t.sub.R=3.60 min (Method 6).
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phe-
nyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic acid
(Compound 635)
##STR00280##
To a stirred solution of (S)-methyl
1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl-
)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (341 mg,
0.489 mmol) in THF (10 mL) was added sulfuric acid (3 mL of a 5 M
aqueous solution, 15 mmol). After 24 h, the mixture was diluted
with water (100 mL) and extracted with EA (2.times.100 mL). The
combined organic extracts were washed with brine (50 mL), dried
over MgSO.sub.4 and solvents evaporated. Column chromatography
(AcOH/EA/DCM/iso-hexanes) gave 233 mg (70%) of
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(hep-
tyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic
acid (Compound 635) as a white solid. LCMS-ESI (m/z) calculated for
C.sub.39H.sub.46N.sub.4O.sub.5S: 682.3; no m/z observed,
t.sub.R=10.17 min (Method 10). The chiral purity was >98% e.e.
(Chiral Method). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 12.75 (s,
1H), 9.17 (d, J=1.8 Hz, 2H), 8.77 (app dd, J=8.3, 2.7 Hz, 1H), 8.32
(dd, J=8.2, 4.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 7.70 (d, J=3.9 Hz,
1H), 7.47-7.52 (m, 2H), 7.11-7.07 (m, 2H), 6.93 (app dd, J=3.9, 1.4
Hz, 1H), 4.70-4.63 (m, 1H), 4.43 (t, J=9.0 Hz, 0.5H), 4.30 (dd,
J=8.7, 6.0 Hz, 0.5H), 4.21 (t, J=8.9 Hz, 0.5H), 4.15 (dd, J=8.5,
6.3 Hz, 0.5H), 4.08-3.99 (m, 3H), 3.47-3.40 (m, 1H), 3.93-3.87 (m,
1H), 3.15-3.01 (m, 2H), 1.77-1.70 (m, 2H), 1.49-1.16 (m, 17H), 0.88
(t, J=6.8 Hz, 3H).
Compound 642 was prepared from
(2S,3R)-2-amino-3-hydroxy-3-phenylpropanoic acid and
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)-pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using
General Procedures 26, 7 and 8 sequentially.
Compounds 650 and 654 were prepared from
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)ph-
enyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic acid
(Compound 635) using General Procedure 7.
Compound 649 was prepared from methyl
(S)-2-(N-(1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyl-
oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carbonyl)sulfamoyl)-
acetate (Compound 654) using General Procedure 4.
threo-methyl 2-amino-3-hydroxy-3-phenylpropanoate HCl
##STR00281##
Prepared using General Procedure 22: To a stirred solution of
threo-2-amino-3-hydroxy-3-phenylpropanoic acid (7 g, 38.6 mmol) in
MeOH (20 mL) was added chlorotrimethylsilane (19.8 mL, 155 mmol).
The mixture was heated under reflux for 16 h then solvents
evaporated to afford 8.95 g (100%) of threo-methyl
2-amino-3-hydroxy-3-phenylpropanoate HCl. LCMS-ESI (m/z) calculated
for C.sub.10H.sub.13NO.sub.3; 195.1; found 196.0 [M+H].sup.+,
t.sub.R=0.18 min (Method 10). .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 8.45 (s, 3H), 7.42-7.31 (m, 5H), 5.03 (d, J=5.4 Hz, 1H),
4.18 (app t, J=5.4 Hz, 1H), 3.63 (s, 3H).
threo-methyl
2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate
##STR00282##
Prepared using General Procedure 23: To a stirred mixture of
threo-methyl 2-amino-3-hydroxy-3-phenylpropanoate, HCl (1.1 g, 4.75
mmol), MeOH (10 mL) and NaHCO.sub.3 (8.44 mL of a 0.9 M aqueous
solution, 7.60 mmol) was added di-tert-butyl dicarbonate (1.451 g,
6.65 mmol). After 3 h, the bulk of the MeOH was evaporated under
reduced pressure and the aqueous extracted with diethyl ether
(2.times.40 mL). The combined organic extracts were dried over
MgSO.sub.4 and solvents evaporated. The residue was re-slurried
from iso-hexanes and the solid collected by filtration to afford
1.1 g (78%) of threo-methyl
2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate.
LCMS-ESI (m/z) calculated for C.sub.15H.sub.21NO.sub.5: 295.1;
found 318.0 [M+Na].sup.+, t.sub.R=4.45 min (Method 10).
methyl 2-((tert-butoxycarbonyl)amino)-3-oxo-3-phenylpropanoate
##STR00283##
Prepared using General Procedure 24: To a stirred solution of
oxalyl chloride (0.47 ml, 5.42 mmol) in DCM (50 mL) at -78.degree.
C. was added DMSO (0.77 mL, 10.8 mmol) and the reaction stirred for
10 mins. This was then treated with a pre-cooled solution of
threo-methyl
2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate (1 g,
3.39 mmol) in DCM (20 mL). After 2 h, DIEA (2.96 mL, 16.93 mmol)
was added and the mixture allowed to warm to 0.degree. C. After 1
h, the mixture was washed with NH.sub.4Cl (2.times.20 mL of a
saturated aqueous solution) and the organics dried over MgSO.sub.4
and solvents evaporated to afford 964 mg (97%) of methyl
2-((tert-butoxycarbonyl)amino)-3-oxo-3-phenylpropanoate. LCMS-ESI
(m/z) calculated for C.sub.15H.sub.19NO.sub.5: 293.1; found 316.0
[M+Na].sup.+, t.sub.R=2.15 min (Method 11).
erythro-methyl
2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate
##STR00284##
Prepared using General Procedure 25: To a stirred solution of
methyl 2-((tert-butoxycarbonyl)amino)-3-oxo-3-phenylpropanoate (0.5
g, 1.705 mmol) in MeOH (10 mL) at -78.degree. C. was added sodium
borohydride (0.045 g, 1.193 mmol). After 0.5 h, the reaction was
quenched with NH.sub.4Cl (8 mL of a saturated aqueous solution) and
the MeOH evaporated under reduce pressure. The mixture was
extracted with DCM (2.times.30 mL) and the combined organic
extracts dried over MgSO.sub.4 and solvents evaporated. The residue
was purified by column chromatography (EA/iso-hexanes) to afford
312 mg (62%) of erythro-methyl
2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate.
LCMS-ESI (m/z) calculated for C.sub.15H.sub.21NO.sub.5: 295.1;
found 318.0 [M+Na].sup.+, t.sub.R=1.84 min (Method 11).
erythro-methyl 2-amino-3-hydroxy-3-phenylpropanoate
##STR00285##
Prepared using General Procedure 8: To a stirred solution of
erythro-methyl
2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate (0.3 g,
1.02 mmol) in DCM (15 mL) was added TFA (1.57 mL, 20.32 mmol).
After 3 h, solvents were evaporated and the residue purified by
strong-cation-exchange ion exchange chromatography to afford 195 mg
(98%) of erythro-methyl 2-amino-3-hydroxy-3-phenylpropanoate as a
white solid. LCMS-ESI (m/z) calculated for
C.sub.10H.sub.13NO.sub.3: 195.2; found 196.0 [M+Na].sup.+,
t.sub.R=0.19 min (Method 11).
Compound 651 was prepared from
erythro-2-amino-3-hydroxy-3-phenylpropanoic acid and
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)-pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using
General Procedures 7 and 4 sequentially.
Compound 663 was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) and
tert-butyl N.sup.4-methyl-D-asparaginate (INT-46) using General
Procedures 7 then 8.
Compound 665 was prepared from
erythro-2-amino-3-hydroxy-3-phenylpropanoic acid and
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)-pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using
General Procedures 7 and 4 sequentially, followed by chiral
preparative HPLC.
methyl
(2,3-erythro)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-
-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-3-hydroxy-3-ph-
enylpropanoate
##STR00286##
Prepared using General Procedure 7: To a stirred solution of
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)-propanoic acid (Compound 192) (578 mg,
0.963 mmol) and erythro-methyl 2-amino-3-hydroxy-3-phenylpropanoate
(188 mg, 0.963 mmol) in DMF (8 mL) was added DIEA (503 .mu.L, 2.89
mmol). The mixture was cooled to 0.degree. C. and treated with HATU
(384 mg, 1.01 mmol), added portionwise. The cooling bath was
removed and the reaction allowed to stir for 2 h. The mixture was
treated with citric acid (100 mL of a 10% w/v aqueous solution) and
extracted with EA (3.times.20 mL). The combined organic extracts
were dried over MgSO.sub.4 and solvents evaporated. Column
chromatography (EA/iso-hexanes) gave 654 mg (87%) of
methyl(2,3-erythro)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-
-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-3-hydroxy-3-ph-
enylpropanoate as a white solid. LCMS-ESI (m/z) calculated for
C.sub.45H.sub.52N.sub.4O.sub.6S: 776.4; no m/z observed,
t.sub.R=3.24 min (Method 11).
(2R,3R)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(hepty-
loxy)phenyl)-pyrimidin-2-yl)phenyl)propanamido)-3-hydroxy-3-phenylpropanoi-
c acid (Compound 666)
##STR00287##
Prepared using General Procedure 4: To a stirred solution of
methyl(2,3-erythro)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-
-(5-(4-(heptyloxy)-phenyl)pyrimidin-2-yl)phenyl)propanamido)-3-hydroxy-3-p-
henylpropanoate (327 mg, 0.421 mmol) in THF (5 mL) was added LiOH
(231 .mu.L of a 2 M aqueous solution, 0.463 mmol). After 30 minutes
the mixture was poured into citric acid (25 mL of a 10% w/v aqueous
solution) and extracted with DCM (3.times.30 mL). The combined
organic extracts were dried over MgSO.sub.4 and solvents
evaporated. The residue was purified by column chromatography
(AcOH/MeOH/DCM) then preparative chiral HPLC to afford 15 mg (5%)
of
(2R,3R)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(hept-
yloxy)-phenyl)pyrimidin-2-yl)phenyl)propanamido)-3-hydroxy-3-phenylpropano-
ic acid (Compound 666). LCMS-ESI (m/z) calculated for
C.sub.44H.sub.50N.sub.4O.sub.6S: 762.4; no m/z observed,
t.sub.R=10.68 min (Method 10). The chiral purity was >70% d.e.
(Chiral Method 2). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 12.71 (s,
1H), 9.15 (s, 2H), 8.51 (d, J=9.3 Hz, 1H), 8.42 (d, J=9.0 Hz, 1H),
8.27-8.23 (m, 2H), 7.80-7.77 (m, 2H), 7.61 (d, J=3.9 Hz, 1H),
7.42-7.37 (m, 4H), 7.27-7.20 (m, 3H), 7.10-7.08 (m, 2H), 6.89 (d,
J=3.9 Hz, 1H), 5.81 (s, 1H), 4.80 (d, J=8.8 Hz, 1H), 4.68-4.62 (m,
1H), 4.55 (t, J=9.0 Hz, 1H), 4.04 (t, J=6.5 Hz, 2H), 2.59-2.52 (m,
2H), 1.80-1.68 (m, 2H), 1.43-1.29 (m, 17H), 0.94-0.83 (m, 3H).
(2R,3S)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(hepty-
loxy)phenyl)pyrimidin-2-yl)phenyl)propanamido)-3-hydroxy-3-phenylpropanoic
acid (Compound 667)
##STR00288##
Prepared using General Procedures 7 and 4: To a stirred solution of
threo-methyl 2-amino-3-hydroxy-3-phenylpropanoate (50 mg, 0.256
mmol) and
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) (140 mg,
0.233 mmol) in DMF (3 mL) was added DIEA (122 .mu.L, 0.699 mmol)
and the mixture cooled to 0.degree. C. HATU (97 mg, 0.256 mmol) was
added portionwise and the mixture allowed to warm to room
temperature over 2 h. The mixture was treated with citric acid (40
mL of a 5% w/v aqueous solution) and the liquid decanted. The
aqueous was extracted with EA (50 mL) and this used to dissolve the
solid residue. This solution was diluted with toluene (5 mL) and
solvents evaporated. The residue was purified by column
chromatography (ACN/DCM). The intermediate ester thus obtained was
dissolved in THF/MeOH (1:1, 3 mL) and allowed to stir with LiOH
(0.23 mL of a 2 M aqueous solution, 0.46 mmol). After 16 h, further
LiOH (0.58 mL of a 2 M aqueous solution, 1.17 mmol) was charged.
After an additional 1 h, the mixture was treated with citric acid
(20 mL of a 10% w/v aqueous solution) and the precipitate collected
by filtration. Purification by preparative chiral HPLC gave 5 mg
(3%) of
(2R,3S)-2((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(hepty-
loxy)phenyl)pyrimidin-2-yl)-phenyl)propanamido)-3-hydroxy-3-phenylpropanoi-
c acid (Compound 667). LCMS-ESI (m/z) calculated for
C.sub.44H.sub.50N.sub.4O.sub.6S: 762.4; no m/z observed,
t.sub.R=10.63 min (Method 10). The chiral purity was <80% d.e.
(chiral Method 2). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 12.71 (s,
1H), 9.08 (s, 2H), 8.30 (dd, J=17.6, 9.1 Hz, 2H), 8.24-8.13 (m,
2H), 7.78-7.66 (m, 2H), 7.53 (d, J=3.9 Hz, 1H), 7.32 (app ddd,
J=16.7, 7.6, 1.8 Hz, 4H), 7.25-7.08 (m, 3H), 7.08-6.90 (m, 2H),
6.83 (d, J=3.8 Hz, 1H), 5.81 (d, J=4.6 Hz, 1H), 5.17 (s, 1H), 4.72
(ddd, J=11.0, 9.0, 3.9 Hz, 1H), 4.50 (dd, J=9.2, 2.8 Hz, 1H), 3.96
(t, J=6.5 Hz, 2H), 2.78 (dd, J=13.8, 3.7 Hz, 1H), 2.68-2.54 (m,
1H), 1.75-1.59 (m, 2H), 1.42-1.12 (m, 17H), 0.89-0.75 (m, 3H).
Compound 670 was prepared from methyl
2-(4-(tert-butyl)benzamido)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)phenyl)acetate (INT-34) and
5-(4-(heptyloxy)phenyl)-2-iodopyrimidine using General Procedure
10.
Compound 671 was prepared from 2-chloroquinolin-6-ol and
1-bromoheptane using General Procedure 12, General Procedure 10
using tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13), then General Procedure 8.
Compound 672 was prepared from 3-chloroisoquinolin-7-ol and
1-bromoheptane using General Procedure 12, General Procedure 10
using tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13), and General Procedure 8.
Compound 673 was prepared from 2-chloroquinazolin-6-ol and
1-bromoheptane using General Procedure 12, General Procedure 10
using tert-butyl
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl)propanoate (INT-13), then General Procedure 8.
Compound 674 and 693 were prepared from tert-butyl
(S)-3-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)pro-
panamido)propanoate (INT-28) using General Procedure 11 then 8.
Compounds 675-691, 694, 695 and 696 were prepared from tert-butyl
(S)-3-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)pro-
panamido)propanoate (INT-28) using General Procedures 10 and 8.
Compounds 692, 744-748, 751-755, 758-760 were prepared from
commercial nitriles using General Procedure 2, then General
Procedure 5 using
(S)-2-(4-(3-((3-(tert-butoxy)-3-oxopropyl)amino)-2-(4-(tert-butyl)benzami-
do)-3-oxopropyl)phenyl)pyrimidine-5-carboxylic acid (INT-33) and
General Procedure 8.
Compounds 697-705 were prepared by coupling commercial phenol
boronic acids and tert-butyl
(S)-3-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)pro-
panamido)propanoate (INT-28) using General Procedure 10 followed by
General Procedures 12 and 8.
Compounds 706-716, and 803 were prepared from tert-butyl
(S)-3-(2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)-pyrimidin-2--
yl)phenyl)propanamido)propanoate (INT-29) using General Procedures
12 and 8.
Compounds 717-742 and 800 were prepared from tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)-prop-
anoyl)-D-alaninate (INT-32) using General Procedures 10 then 8.
Compounds 743, 749, 750, 756 and 757 were prepared from
(S)-2-(4-(3-((3-(tert-butoxy)-3-oxopropyl)amino)-2-(4-(tert-butyl)benzami-
do)-3-oxopropyl)phenyl)pyrimidine-5-carboxylic acid (INT-33) using
General Procedure 5 and 8.
Compounds 761-769 were prepared from methyl
(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-
-2-carboxamido)propanoyl)pyrrolidine-3-carboxylate (INT-35) using
General Procedures 10 then 4.
Compounds 770 and 771 were prepared from tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)p-
yrimidin-2-yl)phenyl)propanoyl)-D-alaninate (INT-36) using General
Procedures 12 then 8.
Compounds 772-774 were prepared from methyl
(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyph-
enyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylate
(INT-37) using General Procedures 12 then 4.
Compound 775 was prepared from tert-butyl
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylate (INT-38) using General
Procedures 10 then 8.
Compound 776 was prepared from (3-methyl-4-hydroxyphenyl)boronic
acid and tert-butyl
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylate (INT-38) using General
Procedure 10, then with 1-bromoheptane using General Procedure 12
then 8.
Compounds 777-789 were prepared from tert-butyl
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylate (INT-38) using General
Procedures 10 then 8.
Compound 790 was prepared from (4-hydroxy-2-methylphenyl)boronic
acid and (R)-tert-butyl
2-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-
propanamido)propanoate (INT-42) using General Procedures 10, 12,
18, 7 and 8 sequentially.
Compound 791 was prepared from 4-bromo-3,5-dimethylphenol and
(R)-tert-butyl
2-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-
propanamido)propanoate (INT-42) using General Procedures 12, 27,
10, 18, 7 and 8 sequentially.
Compounds 792-794 were prepared from tert-butyl
((S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)-
phenyl)propanoyl)-D-alaninate (INT-45) using General Procedures 12
then 8.
Compounds 795-797 and 799 were prepared from tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl-
)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (INT-48)
using General Procedures 12 then 8.
tert-butyl(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((4--
methylpentyl)oxy)phenyl-)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carbo-
xylate
##STR00289##
Prepared using General Procedure 12: To a stirred solution of
tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl-
)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (INT-48)
(300 mg, 0.479 mmol) in DMF (5 mL) was added Cs.sub.2CO.sub.3 (197
mg, 0.58 mmol) and 1-bromo-4-methylpentane (158 mg, 0.96 mmol). The
reaction mixture was stirred for 18 h at 65.degree. C. then diluted
with aq. NaHCO.sub.3 (100 ml, saturated) and extracted with EA
(2.times.100 mL). The combined organic layers were dried
(Na.sub.2SO.sub.4), concentrated, and purified by column
chromatography (EA/hexane) to afford 188 mg (54%) of tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((4-methylpen-
tyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate.
LCMS-ESI (m/z) calculated for C.sub.42H.sub.52N.sub.4O.sub.5S:
724.96; found 725.3 [M+H].sup.+, t.sub.R=12.71 min (Method 16).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.97 (d, J=7.5 Hz, 2H),
8.45 (d, J=5.5 Hz, 2H), 7.55 (s, 2H), 7.49-7.31 (m, 3H), 7.05 (d,
J=6.6 Hz, 2H), 6.82 (s, 1H), 6.68 (d, J=28.8 Hz, 1H), 4.82 (s, 1H),
4.30 (s, 0.5H), 4.07 (m, 5.5H), 3.56 (s, 0.5H), 3.31-3.09 (m, 2H),
2.91 (s, 0.5H), 1.83 (s, 2H), 1.60 (d, J=25.3 Hz, 1H), 1.40 (s,
16H), 1.29 (s, 4H), 0.95 (s, 6H).
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((4-methylpent-
yl)oxy)phenyl)-pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic
acid (Compound 798)
##STR00290##
Prepared using General Procedure 8: To a stirred solution of
tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((4-methylpen-
tyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
(188 mg, 0.26 mmol), in DCM (2 mL) was added TFA (2 mL). The
mixture was stirred for 4 h then concentrated. The resulting solid
was dissolved in DCM (10 mL) and concentrated (5.times.) to remove
excess TFA, affording 169 mg (98%) of
1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((4-methylpentyl)-
oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic
acid (Compound 798) as a yellow solid. LCMS-ESI (m/z) calculated
for C.sub.38H.sub.44N.sub.4O.sub.5S: 668.85; found 669.3
[M+H].sup.+, t.sub.R=9.121 min (Method 16). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.17 (s, 2H), 8.12 (d, J=7.8 Hz, 2H), 7.58 (m,
3H), 7.45 (m, 1H), 7.42 (m, 2H), 7.06 (m, 2H), 6.84 (m, 1H), 4.71
(d, J=7.7 Hz, 1H), 4.33-4.14 (m, 2H), 4.08 (dd, J=19.8, 9.1 Hz,
2H), 4.03 (t, J=6.6 Hz, 2H), 3.30 (dd, J=12.5, 4.2 Hz, 1H), 3.06
(t, J=11.9 Hz, 1H), 2.91 (s, 1H), 1.91-1.76 (m, 2H), 1.64 (dt,
J=13.0, 6.6 Hz, 1H), 1.43-1.33 (m, 11H), 0.95 (d, J=6.6 Hz,
6H).
Compound 801 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadi-
azol-3-yl)phenyl)propanoic acid (Compound 2) using General
Procedures 7 then 8.
Compound 802 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-thiad-
iazol-2-yl)phenyl)propanoic acid (Compound 83) using General
Procedures 7 then 8.
Compound 804 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)piperazin-1--
yl)phenyl)propanoic acid (Compound 267) using General Procedures 7
and 8.
Compounds 806 and 807 were prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(6-(heptyloxy)quinolin-2-yl)phenyl)p-
ropanoic acid (Compound 671) using General Procedures 7 then 8.
Compound 808 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(7-(heptyloxy)isoquinolin-3-yl)pheny-
l)propanoic acid (Compound 672) using General Procedures 7 then
8.
Compound 809 and 810 were prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(6-(heptyloxy)quinazolin-2-yl)phenyl-
)propanoic acid (Compound 673) using General Procedures 7 then
8.
Compound 811 was prepared from (S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)propanoate (INT-6) and 5-bromo-2-iodopyridine using
General Procedures 10, 10, 8, 7, 18, 7 and 8 sequentially.
Compound 812 was prepared from 2-bromo-5-iodo-3-methylpyridine and
(S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)propanoate (INT-6) using General Procedures 10, 10,
8, 7, 18, 7 and 8 sequentially.
Compounds 813-830 and 832-843 were prepared from tert-butyl
((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl-
)-D-alaninate (INT-24) using General Procedures 7 then 8.
Compounds 844, 853 and 855-868 were prepared from methyl
(S)-1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)pro-
panoyl)pyrrolidine-3-carboxylate (INT-39) using General Procedures
7 then 8.
Compounds 869 and 870 were prepared from
(S)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-2-(4-(pyrrolidin--
1-yl)benzamido)propanoic acid (Compound 90) using General
Procedures 7 then 8.
Compounds 871-879 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 7 then 8.
Compounds 880-882 and 888 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 7 then 4.
Compound 883 was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) and methyl
(2S, 3S)-2-amino-3-((tert-butoxycarbonyl)amino)-3-phenylpropanoate
using General Procedures 7, 4 then 8.
Compounds 884, 885 and 887 were prepared from
(S)-1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptylox-
y)phenyl)pyrimidin-2-yl)phenyl)propanoyl)pyrrolidine-3-carboxylic
acid (Compound 349) using General Procedure 7.
Compound 886 was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedure 7.
Compound 889 was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 7 then 8.
methyl 2-amino-3-methoxy-3-phenylpropanoate
##STR00291##
To a stirring solution of threo-methyl
2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-phenylpropanoate (148
mg, 0.5 mmol) in DCM (5 mL) was added proton sponge (430 .mu.L, 2.0
mmol), 4 .ANG. molecular sieves (520 mg) and trimethyloxonium
tetrafluoroborate (260 mg). The reaction mixture was stirred
vigorously at room temperature for 24 hours and the solids were
removed by filtration. The filtrate was washed with 10% aqueous
copper sulfate (10 mL), saturated aqueous ammonium chloride (10
mL), saturated aqueous sodium bicarbonate (10 mL), and brine (10
mL). The organic layer was dried over magnesium sulfate and
concentrated. The crude compound was purified by column
chromatography (0-100% EA in hexanes) to afford 86 mg of methyl
2-((tert-butoxycarbonyl)amino)-3-methoxy-3-phenylpropanoate which
was dissolved in DCM (1 mL) and treated with TFA (425 After 1 hour,
all solvent was removed to give 96 mg (59%) of methyl
2-amino-3-methoxy-3-phenylpropanoate. LCMS-ESI (m/z) calculated for
C.sub.11H.sub.15NO.sub.3: 209.1; found 210.1 [M+H].sup.+,
t.sub.R=1.46 min (Method 16).
Compound 890 was prepared from methyl
2-amino-3-methoxy-3-phenylpropanoate and
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 7 then 4.
Compound 891 was prepared from 1-tert-butyl 3-methyl
piperazine-1,3-dicarboxylate and
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 7, 4 then 8.
Compound 892 was prepared from 1,3-pyrrolidinedicarboxylic acid,
5-methyl-, 1-(1,1-dimethylethyl) ester using General Procedures 22
then 8, and
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptylox-
y)phenyl)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using
General Procedures 7 then 4.
Compound 893 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2--
yl)phenyl)propanoic acid (Compound 85) and
1,3-pyrrolidinedicarboxylic acid, 5-methyl-, 1-(1,1-dimethylethyl)
ester using General Procedures 22, 8, 7 then 4.
Compound 894 was prepared from
3-(aminomethyl)-1-methylpyrrolidin-3-ol and
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)p-
henyl)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using
General Procedure 7.
Compound 895 was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) and
(2R,3R)-methyl 2-amino-3-hydroxybutanoate hydrochloride using
General Procedures 7, 28 and 29 sequentially.
Compounds 896-899 were prepared from 2-amino-3-phenylbutanoic acid
using General Procedure 22, and
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)propanoic acid (INT-22) using General Procedures 7,
18, 7 and 4 sequentially.
Compounds 900-908 and 911-918 were prepared from a suitable
aminoalcohol, prepared using General Procedure 30, and
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 7 and 8 sequentially.
Compound 909 was prepared from (2S,
3S)-2-((tert-butoxycarbonyl)amino)-3-phenylbutanoic acid using
General Procedure 22, and
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 7 and 4 sequentially.
Compound 910 was prepared from (2R,
3R)-2-((tert-butoxycarbonyl)amino)-3-phenylbutanoic acid using
General Procedure 22, and
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 7 and 4 sequentially.
Compounds 919-922, 944 and 945 were prepared from tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl-
)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (INT-48)
using General Procedures 12 then 8.
tert-butyl
2-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thi-
ophene-2-carboxamido)propanamido)-3-(tert-butoxy)-3-phenylpropanoate
##STR00292##
Prepared using General Procedure 7. To a stirring solution of
tert-butyl 2-amino-3-(tert-butoxy)-3-phenylpropanoate (198 mg, 0.7
mmol) in DMF (5 mL) were added DIEA (267 .mu.L, 1.54 mmol), and
tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoate (INT-17) (300 mg, 0.6 mmol). The solution was
cooled to 0.degree. C. at ice bath and then HATU (245 mg, 0.6 mmol)
was added. The reaction was stirred for 1 hour at 0.degree. C. and
then warmed to RT with stirring for 2 hours. The reaction solution
was diluted with aqueous NaHCO.sub.3 (50 mL) and extracted with EA
(3.times.50 mL). The combined organics were dried over
Na.sub.2SO.sub.4 and purified by chromatography (EA/Hexanes) to
afford 308 mg (67%) of tert-butyl
2-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanamido)-3-(tert-butoxy)-3-phenylpropanoate.
LCMS-ESI (m/z) calculated for C.sub.39H.sub.47BrN.sub.4O.sub.5S:
763.79; found 764.2 [M+H]+, t.sub.R=4.64 min. (Method 15).
Compounds 925-934 and 943 were prepared from tert-butyl
2-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanamido)-3-(tert-butoxy)-3-phenylpropanoate using
General Procedure 10 then 8.
tert-butyl
3-(tert-butoxy)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido-
)-3-(4-(5-(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)-3-phenylprop-
anoate (INT-51)
##STR00293##
To a 100 ml flask were added (4-hydroxyphenyl)boronic acid (63 mg,
0.5 mmol), sodium carbonate decahydrate (217 mg, 0.8 mmol),
tert-butyl
2-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanamido)-3-(tert-butoxy)-3-phenylpropanoate (290 mg,
0.4 mmol), Pd(dppf)Cl.sub.2 (28 mg, 0.04 mmol), dioxane (10.0 mL),
and water (2.0 mL). The reaction mixture was heated to 80.degree.
C. overnight. The reaction mixture was dried under reduced pressure
to remove the solvent and diluted in DCM (20 mL). The mixture was
washed with aqueous NaHCO.sub.3 (3.times.10 mL). The combined
organics were dried over Na.sub.2SO.sub.4 and evaporated to afford
309 mg (106%) of crude tert-butyl
3-(tert-butoxy)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5--
(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)-3-phenylpropanoate
(INT-51) which was used without further purification. LCMS-ESI
(m/z) calculated for C.sub.45H.sub.52N.sub.4O.sub.6S: 776.9; found
721 [M-tBuO]+, t.sub.R=11.03 min. (Method 14).
Compounds 923, 924 and 935-942 were prepared from tert-butyl
3-(tert-butoxy)-2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5--
(4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanamido)-3-phenylpropanoate
(INT-51) using General Procedure 12 followed by General Procedure
8.
Compound 946 was prepared from 2-bromo-5-iodo-3-methylpyridine and
4-(heptyloxy)phenyl boronic acid using General Procedure 10, and
then with (S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)propanoate (INT-6) using General Procedures 10, 18,
7 and 8 sequentially.
methyl
2-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)-
pyrimidin 2-yl)phenyl)propanamido)-3-hydroxy-3-phenylpropanoate
##STR00294##
Prepared using General Procedure 7. To a stirring solution of
methyl 2-amino-3-hydroxy-3-phenylpropanoate hydrochloride (0.92 g,
3.96 mmol) in DMF (10 mL) were added DIEA (0.85 g, 6.6 mmol) and
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-
-2-yl)phenyl)propanoic acid (INT-22) (1.50 g, 2.64 mmol). The
solution was cooled to 0.degree. C. and HATU (0.93 g, 3.96 mmol) in
2 mL DMF solution was slowly added. The reaction was stirred 1 hour
at 0.degree. C. and then warmed to RT with stirring for 2 hours.
The mixture was diluted with DCM (3.times.20 mL) and washed with
aqueous NaHCO.sub.3 (3.times.10 mL). The combined organics were
dried over MgSO.sub.4. The organic layer was concentrated to afford
1.5 g (76%) of methyl
2-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimi-
din-2-yl)phenyl)propanamido)-3-hydroxy-3-phenylpropanoate as a
solid powder. LCMS-ESI (m/z) calculated for
C.sub.44H.sub.48N.sub.4O.sub.7: 744.4; found 745.3 [M+H].sup.+,
t.sub.R=4.57 min (Method 16). .sup.1H NMR (400 MHz, DMSO) .delta.
9.20 (s, 2H), 8.50 (d, J=8.9 Hz, 1H), 8.40-8.14 (m, 2H), 7.82 (d,
J=8.7 Hz, 2H), 7.59 (d, J=9.0 Hz, 1H), 7.31 (dddd, J=43.2, 15.1,
13.9, 7.0 Hz, 12H), 7.10 (d, J=8.8 Hz, 2H), 6.01 (dd, J=14.5, 4.6
Hz, 1H), 5.33-5.03 (m, 1H), 5.04-4.77 (m, 2H), 4.67 (dd, J=9.0, 3.1
Hz, 0.5H), 4.56 (dd, J=8.5, 3.3 Hz, 0.5H), 4.43 (dd, J=19.9, 8.5
Hz, 1H), 4.04 (t, J=6.5 Hz, 2H), 3.70 (s, 1H), 3.62 (s, 2H), 2.72
(dd, J=15.4, 6.7 Hz, 1H), 2.47-2.29 (m, 1H), 1.87-1.58 (m, 2H),
1.43 (dd, J=15.1, 7.1 Hz, 2H), 1.33 (dd, J=17.5, 8.9 Hz, 6H), 0.88
(t, J=6.8 Hz, 3H).
methyl
2-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)p-
ropanamido)-3-hydroxy-3-phenylpropanoate (INT-49)
##STR00295##
Prepared using General Procedure 18. To a stirring solution of
methyl
2-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimi-
din-2-yl)phenyl)propanamido)-3-hydroxy-3-phenylpropanoate (1.3 g,
1.75 mmol) in THF (25 mL) was added Pd/C (200.0 mg, 10% Pd/C). The
solution was degassed and then stirred under H.sub.2 at room
temperature for 18 hours. The solution was filtered through celite
and concentrated to afford 0.86 g (81%) of methyl
2-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propana-
mido)-3-hydroxy-3-phenylpropanoate (INT-49) as a solid. LCMS-ESI
(m/z) calculated for C.sub.36H.sub.42N.sub.4O.sub.5: 610.3; found
611.3 [M+H].sup.+, t.sub.R=4.092 min (Method 16). .sup.1H NMR (400
MHz, DMSO) .delta. 9.21 (t, J=2.4 Hz, 2H), 9.12 (dd, J=13.4, 8.9
Hz, 1H), 8.38 (dd, J=13.1, 5.4 Hz, 1H), 8.32-8.20 (m, 1H), 8.01 (d,
J=32.8 Hz, 2H), 7.82 (d, J=8.7 Hz, 2H), 7.49 (dt, J=17.2, 8.9 Hz,
2H), 7.37 (dd, J=15.1, 7.1 Hz, 2H), 7.26 (dt, J=14.4, 7.3 Hz, 1H),
7.14 (dd, J=30.9, 8.1 Hz, 2H), 7.04 (d, J=8.3 Hz, 1H), 5.25 (dd,
J=29.7, 16.8 Hz, 1H), 4.75 (dd, J=9.2, 2.8 Hz, 0.5H), 4.62 (dd,
J=8.4, 3.3 Hz, 0.5H), 4.21 (d, J=15.3 Hz, 1H), 4.04 (t, J=6.5 Hz,
2H), 3.74 (s, 2H), 3.67 (d, J=5.8 Hz, 1H), 3.04-2.75 (m, 1H), 2.55
(s, 3H), 1.81-1.66 (m, 2H), 1.51-1.38 (m, 2H), 1.33 (dd, J=15.7,
10.4 Hz, 6H), 0.88 (t, J=6.8 Hz, 3H).
Compounds 947-960 were prepared from methyl
2-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propana-
mido)-3-hydroxy-3-phenylpropanoate (INT-49) using General
Procedures 7 then 4.
Compounds 961-978 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedure 7.
Compounds 984-989, 991 and 1047 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 7 then 8.
Compounds 979-983 and 990 were prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(2',4'-difluoro-[1,1'-biphenyl]-4-
-yl)-1,2,4-oxadiazol-3-yl)phenyl)propanoic acid (Compound 24) using
General Procedures 7 then 8.
Compounds 992-1046 and 1050-1055 were prepared from tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alaninate using General Procedures 10 then
8.
Compounds 1048 and 1049 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 7 then 8.
tert-butyl
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-ethylc-
yclohexyl)-phenyl)pyrimidin-2-yl)phenyl)propanoate
##STR00296##
Prepared using General Procedure 10: A stirred solution of
(S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propano-
ate (INT-7) (20 g, 39.0 mmol) in dioxane (200 mL) was treated with
(4-((1r,4r)-4-ethylcyclohexyl)phenyl)boronic acid (9.97 g, 42.9
mmol) and NaHCO.sub.3 (87 mL of a 0.9 M aqueous solution, 78 mmol).
The mixture was warmed to 40.degree. C., de-gassed, then treated
with PdCl.sub.2dppf (0.714 g, 0.976 mmol) and heated under reflux.
After 3 h, the mixture was allowed to cool then diluted with water
(300 mL) and extracted with DCM (3.times.100 mL). The combined
organics were evaporated and re-slurried from MeOH (250 mL) to
afford 23.5 g (97%) of tert-butyl
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)-
phenyl)pyrimidin-2-yl)phenyl)propanoate as a grey powder. LCMS-ESI
(m/z) calculated for C.sub.39H.sub.45N.sub.3O.sub.4: 619.3; no m/z
observed, t.sub.R=12.33 min (Method 10).
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)p-
henyl)pyrimidin-2-yl)phenyl)propanoic acid
##STR00297##
Prepared using General Procedure 8: A stirred solution of
(S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)phen-
yl)pyrimidin-2-yl)phenyl)propanoate (13.33 g, 21.51 mmol) in DCM
(100 mL) was treated with TFA (50 mL, 21.51 mmol). After 16 h,
solvents were evaporated and the residue further evaporated with
toluene (2.times.50 mL) to afford 12.1 g (100%) of
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)-
phenyl)pyrimidin-2-yl)phenyl)propanoic acid as a white solid.
LCMS-ESI (m/z) calculated for C.sub.35H.sub.37N.sub.3O.sub.4:
563.3; found 564.3 [M+H].sup.+, t.sub.R=3.20 min (Method 11).
tert-butyl
((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-ethyl-
cyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate
##STR00298##
Prepared using General Procedure 7: To a stirred solution of
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)-
phenyl)pyrimidin-2-yl)phenyl)propanoic acid (8.9 g, 15.79 mmol) in
DMF (150 mL) was added (R)-tert-butyl 2-aminopropanoate, HCl (3.44
g, 18.95 mmol) and DIEA (8.27 mL, 47.4 mmol) and the mixture cooled
to 0.degree. C. whereupon HATU (7.20 g, 18.95 mmol) was added in
small portions. After 2 h, the mixture was quenched with 10%
aqueous citric acid (150 mL) and the liquors decanted. The residue
was dissolved in EA (500 mL) and the resulting solution washed
successively with water (100 mL) and brine (100 mL), dried over
MgSO.sub.4 and solvents evaporated. Column chromatography (ACN/DCM)
gave 8 g (73%) of (R)-tert-butyl
2-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-ethylcyclohex-
yl)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate as a yellow
solid. LCMS-ESI (m/z) calculated for
C.sub.42H.sub.50N.sub.4O.sub.5: 690.4; no m/z observed,
t.sub.R=3.04 min (Method 11).
tert-butyl
((S)-2-amino-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)pyrim-
idin-2-yl)phenyl)propanoyl)-D-alaninate
##STR00299##
Prepared using General Procedure 18: A stirred mixture of
(R)-tert-butyl
2-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-ethylcyclohex-
yl)phenyl)pyrimidin-2-yl)phenyl)propanamido)propanoate (8 g, 11.58
mmol) and 10% Pd/C (Johnson and Matthey Type 39 paste 1.23 g) in
THF (100 mL) was hydrogenated at 4 bar. After 6 h, the mixture was
filtered through Celite and evaporated to afford 6.45 g (100%) of
tert-butyl
((S)-2-amino-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)pyrimidin-2-yl)-
phenyl)propanoyl)-D-alaninate. LCMS-ESI (m/z) calculated for
C.sub.34H.sub.44N.sub.4O.sub.3: 556.3; found 557.3 [M+H].sup.+,
t.sub.R=3.26 min (Method 11).
tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,-
4r)-4-ethylcyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate
##STR00300##
Prepared using General Procedure 7: To a stirred solution of
(R)-tert-butyl
2-((S)-2-amino-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)pyrimidin-2-y-
l)phenyl)propanamido)propanoate (6.5 g, 11.68 mmol) and
5-(tert-butyl)thiophene-2-carboxylic acid (2.58 g, 14.01 mmol) in
DMF (80 mL) was added DIEA (6.12 mL, 35.0 mmol) and the mixture
cooled to -5.degree. C. HATU (5.33 g, 14.01 mmol) was added in
small portions such that the internal temperature was maintained
below 0.degree. C. After a further 2 h, the reaction was treated
with 10% aqueous citric acid (50 mL) and water (100 mL). The
liquors were decanted and the precipitate extracted into EA
(3.times.150 mL). The combined organic extracts were washed
successively with water (100 mL) and brine (100 mL), dried over
MgSO.sub.4 and solvents evaporated. The residue was purified by
column chromatography (ACN/DCM) to afford 7.4 g (88%) of tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-ethy-
lcyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate.
LCMS-ESI (m/z) calculated for C.sub.43H.sub.54 N.sub.4O.sub.4S:
722.4; no m/z observed, t.sub.R=3.20 min (Method 11).
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-ethyl-
cyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alanine
(Compounds 1056)
##STR00301##
Prepared using General Procedure 8: To a stirred solution of
(R)-tert-butyl
2-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-et-
hylcyclohexyl)phenyl)-pyrimidin-2-yl)phenyl)propanamido)propanoate
(7.4 g, 10.24 mmol) in DCM (100 mL) was added TFA (47.3 mL). After
16 h, the mixture was diluted with toluene (100 mL) and solvents
evaporated. The residue was purified by column chromatography
(iso-hexanes/DCM/THF/EA/AcOH) to afford a white solid. Re-slurry
from diethyl ether/iso-hexanes gave 5.5 g (81%) of
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-ethy-
lcyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alanine
(Compound 1056). LCMS-ESI (m/z) calculated for
C.sub.39H.sub.46N.sub.4O.sub.4S: 666.3; no m/z observed,
t.sub.R=3.20 min (Method 11). The chiral purity was >95% e.e
(Chiral Method). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 12.61 (s,
1H), 9.17 (s, 2H), 8.53 (d, J=8.8 Hz, 1H), 8.45 (d, J=7.5 Hz, 1H),
8.31 (d, J=8.4 Hz, 2H), 7.79-7.71 (m, 2H), 7.69 (d, J=3.9 Hz, 1H),
7.50 (d, J=8.4 Hz, 2H), 7.45-7.34 (m, 2H), 6.92 (d, J=3.8 Hz, 1H),
4.82 (td, J=9.7, 9.2, 4.5 Hz, 1H), 4.25 (p, J=7.3 Hz, 1H),
3.20-2.98 (m, 2H), 2.58-2.50 (m, 1H), 1.85 (d, J=11.0 Hz, 4H),
1.58-1.41 (m, 2H), 1.34-1.14 (m, 15H), 1.07 (t, J=11.4 Hz, 2H),
0.90 (t, J=7.2 Hz, 3H).
methyl
1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-ethylcy-
clohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
##STR00302##
Prepared using General Procedure 7: To a stirred solution of
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)-
phenyl)pyrimidin-2-yl)phenyl)propanoic acid (12.1 g, 21.5 mmol) and
methyl azetidine-3-carboxylate hydrochloride (10.10 g, 88 mmol) in
DMF (260 mL) at -7.degree. C. was added DIEA (25.5 mL, 146 mmol).
After 10 min, HATU (32.4 g, 85 mmol) was added in small portions
such that the internal temperature was maintained below -5.degree.
C. After 3 h, the reaction was quenched with citric acid (200 mL of
a 10% aqueous solution) and extracted with DCM (3.times.100 mL).
The combined organic extracts were washed with NaHCO.sub.3 (150
mL), dried over MgSO.sub.4 and solvents evaporated. The residue was
re-slurried from EA (200 mL) to afford 12 g (79%) of methyl
1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-ethylcyclohex-
yl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
as a white solid. LCMS-ESI (m/z) calculated for
C.sub.40H.sub.44N.sub.4O.sub.5: 660.3; found 661.3 [M+H].sup.+,
t.sub.R=3.21 min (Method 11).
methyl
1-((S)-2-amino-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)pyrimid-
in-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
##STR00303##
Prepared using General Procedure 18: A stirred mixture of methyl
1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-ethylcyclohex-
yl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
(12.5 g, 18.92 mmol) and 10% Pd/C (1.2 g, Johnson and Matthey Type
39 Paste) in THF (120 mL) and EtOH (12 mL) was hydrogenated under 5
bar. After 16 h, the mixture was diluted with THF (200 mL),
filtered through Celite and solvents evaporated. Column
chromatography (DCM/NH.sub.3/MeOH) gave 7 g (70%) of methyl
1-((S)-2-amino-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)pyrimidin-2-y-
l)phenyl)propanoyl)azetidine-3-carboxylate as a white solid.
LCMS-ESI (m/z) calculated for C.sub.32H.sub.38N.sub.4O.sub.3:
526.3; found 527.3 [M+H].sup.+, t.sub.R=2.35 min (Method 11).
methyl
1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r-
)-4-ethylcyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-car-
boxylate
##STR00304##
Prepared using General Procedure 7: To a stirred solution of
5-(tert-butyl)thiophene-2-carboxylic acid (2.69 g, 14.62 mmol) and
DIEA (9.29 mL, 53.2 mmol) in DMF/DCM (1:1, 70 mL) was added in
small portions HATU (5.31 g, 13.96 mmol), such that the internal
temperature did not exceed 20.degree. C. After 20 min, a solution
of methyl 1-((S)-2-amino-3-(4-(5-(4-((1r,4r)-4-ethyl
cyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
(7 g, 13.29 mmol) in DMF/DCM (1:1, 90 mL) and DIEA (2.32 mL, 13.29
mmol) was added slowly, to maintain internal temperature below
20.degree. C. (ice-water cooling applied). After 1 h, water (100
mL) was added. After a further 1 h, more water (200 mL) was added
and the mixture extracted with DCM (3.times.150 mL). The combined
organic extracts were dried over MgSO.sub.4 and solvents
evaporated. Column chromatography (DCM/iso-hexanes/EA) gave 7.13 g
(78%) of methyl
1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-et-
hylcyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxyla-
te as a white solid. LCMS-ESI (m/z) calculated for
C.sub.41H.sub.48N.sub.4O.sub.4S: 692.3; found 693.3 [M+H].sup.+,
t.sub.R=3.20 min (Method 11).
1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-eth-
ylcyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic
acid (Compound 1057)
##STR00305##
To a stirred solution of methyl
1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-et-
hylcyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxyla-
te (7.14 g, 10.30 mmol) in THF (150 mL) at 0.degree. C. was added
sulfuric acid (82 mL of a 5 M aqueous solution, 412 mmol). After 10
min, the cooling bath was removed. After 16 h, the mixture was
diluted with brine (100 mL) and extracted with DCM (3.times.100
mL). The combined organic extracts were washed with brine
(2.times.100 mL), dried over MgSO.sub.4 and solvents evaporated.
Column chromatography (DCM/iso-hexanes/EA/AcOH) gave 3.5 g (50%) of
1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-et-
hylcyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxyli-
c acid (Compound 1057) as a white solid. LCMS-ESI (m/z) calculated
for C.sub.40H.sub.46N.sub.4O.sub.4S: 678.3; found 679.3
[M+H].sup.+, t.sub.R=3.35 min (Method 11). The chiral purity was
>95% e.e (Chiral Method). .sup.1H NMR (400 MHz, DMSO-d6) .delta.
12.73 (s, 1H), 9.18 (app d, J=1.8 Hz, 2H), 8.77 (app dd, J=8.2, 2.6
Hz, 1H), 8.52-8.17 (m, 2H), 7.76 (d, J=8.1 Hz, 2H), 7.70 (d, J=3.9
Hz, 1H), 7.47 (app dd, J=8.3, 1.5 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H),
6.93 (app dd, J=3.9, 1.4 Hz, 1H), 4.86-4.54 (m, 1H), 4.43 (t,
J=8.0, 0.5H), 4.32-4.28 (m, 0.5H) 4.23-4.14 (m, 1H), 4.11-3.97 (m,
1H), 3.96-3.83 (m, 1H), 3.48-3.40 (m, 0.5H), 3.32-3.29 (m, 0.5H),
3.18-2.98 (m, 2H), 2.58-2.51 (m, 1H), 1.85 (app d, J=10.0 Hz, 4H),
1.53-1.44 (m, 2H), 1.38-1.15 (m, 12H), 1.10-1.01 (m, 2H), 0.90 (t,
J=7.1 Hz, 3H).
tert-butyl
(S)-2-amino-3-(4-(5-(4-((1s,4s)-4-ethylcyclohexyl)phenyl)pyrimi-
din-2-yl)phenyl)propanoate (INT-78)
##STR00306##
Prepared using General Procedure 18: A stirred mixture of
(S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1s,4s)-4-ethylcyclohexyl)phen-
yl)pyrimidin-2-yl)phenyl)propanoate (8.96 g, 14.46 mmol) and 10%
Pd/C (1 g, Johnson and Matthey Type 39 Paste) in THF (100 mL) was
hydrogenated under a balloon. After 40 h, the mixture was diluted
with THF (40 mL) and further 10% Pd/C (1.5 g, Johnson and Matthey
Type 39 Paste) was charged. The mixture was hydrogenated under 4
bar for a further 8 h, then 2 bar for 16 h. The mixture was
filtered through Celite and solvents evaporated to afford 6.65 g
(95%) of tert-butyl
(S)-2-amino-3-(4-(5-(4-((1s,4s)-4-ethylcyclohexyl)phenyl)pyrimidin-2-yl)p-
henyl)propanoate (INT-78). LCMS-ESI (m/z) calculated for
C.sub.31H.sub.39 N.sub.3O.sub.2: 485.3; found 486.3 [M+H].sup.+,
t.sub.R=7.32 min (Method 10).
tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4-
r)-4-ethylcyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoate
##STR00307##
Prepared using General Procedure 7: To a stirred solution of
5-(tert-butyl)thiophene-2-carboxylic acid (2.78 g, 15.06 mmol) and
DIEA (7.58 mL, 41.1 mmol) in DMF (100 mL) was added in small
portions HATU (5.47 g, 14.38 mmol). After 30 min, this mixture was
added to a stirred suspension of (S)-tert-butyl
2-amino-3-(4-(5-(4-((1s,4s)-4-ethylcyclohexyl)phenyl)pyrimidin-2-yl)pheny-
l)propanoate (6.65 g, 13.69 mmol) in DMF (70 mL). After 1 h, the
mixture was quenched with 1 M aqueous HCl (100 mL) and water (150
mL). The product was collected by filtration, washing successively
with water (3.times.100 mL), MeOH (50 mL), iso-hexanes (3.times.50
mL), MeOH (50 mL) and iso-hexanes (50 mL) to afford 7.95 g (89%) of
tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-ethyl-
cyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoate. LCMS-ESI (m/z)
calculated for C.sub.40H.sub.49 N.sub.3O.sub.3S: 651.4; found 652.3
[M+H].sup.+, t.sub.R=3.70 min (Method 6).
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-ethylc-
yclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoic acid (Compound
1058)
##STR00308##
Prepared using General Procedure 8: To a stirred solution of
(S)-tert-butyl
2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-ethylcycl-
ohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoate (3.60 g, 5.52 mmol)
in DCM (23 mL) was added TFA (13 mL). After 4 h, the mixture was
poured onto ice-water (200 mL) and extracted with DCM (3.times.75
mL). The solvents were evaporated and the residue purified by
column chromatography (DCM/EA/AcOH) to afford a white solid that
was re-slurried from Et.sub.2O to afford 2.66 g (81%) of
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-ethyl-
cyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoic acid (Compound
1058). LCMS-ESI (m/z) calculated for
C.sub.36H.sub.4N.sub.3O.sub.3S: 595.3; no m/z observed,
t.sub.R=11.33 min (Method 10). The chiral purity was >95% e.e
(Chiral Method). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 12.88 (s,
1H), 9.18 (s, 2H), 8.68 (d, J=8.3 Hz, 1H), 8.37-8.30 (m, 2H), 7.76
(d, J=8.3 Hz, 2H), 7.64 (d, J=3.9 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H),
7.43-7.36 (m, 2H), 6.93 (d, J=3.9 Hz, 1H), 4.67-4.12 (m, 1H), 3.27
(dd, J=13.9, 4.5 Hz, 1H), 3.12 (dd, J=13.9, 10.6 Hz, 1H), 2.57-2.46
(m, 1H), 1.85 (d, J=9.8 Hz, 4H), 1.55-1.41 (m, 2H), 1.32 (s, 12H),
1.07 (dd, J=13.2, 10.0 Hz, 2H), 0.90 (t, J=7.2 Hz, 3H).
1-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)piperazine (INT-69)
##STR00309##
To a stirred solution of tert-butyl piperazine-1-carboxylate (870
mg, 4.67 mmol) in DCM (60 mL) was added
(4((1r,4r)-4-ethylcyclohexyl)phenyl)boronic acid (2.2 g, 9.34
mmol), DIEA (3.15 mL, 18.68 mmol) Cu(OAc).sub.2 (1.73 g, 9.34 mmol)
and molecular sieves (4 .ANG. powder). The mixture was allowed to
stir in air for 16 h then diluted with DCM (50 mL) and filtered.
The liquors were washed successively with saturated aqueous
NaHCO.sub.3 (50 mL) and brine (50 mL), dried over MgSO.sub.4 and
solvents evaporated. The residue was taken up in dioxane (20 mL)
then stirred with HCl (11.7 mL of a 4 M solution in dioxane, 46.7
mmol). After 16 h, the mixture was poured into water (100 mL),
basified with 1 M NaOH and extracted with DCM (3.times.150 mL). The
solvents were evaporated and the resulting solid re-slurried from
ACN. The liquors were evaporated and purified by column
chromatography to afford 550 mg (42%) of
1-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)piperazine (INT-69).
LCMS-ESI (m/z) calculated for C.sub.18H.sub.28N.sub.2: 272.2; found
273.4 [M+H].sup.+, t.sub.R=1.80 min (Method 11).
Compound 1059 was prepared from tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(((trifluoromethyl)sul-
fonyl)oxy)phenyl)propanoate (INT-15) and
1-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)piperazine (INT-69) using
General Procedures 11 and 8 sequentially.
Compound 1060 was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4-(4-((1r,4r)-4-ethyl-
cyclohexyl)phenyl)piperazin-1-yl)phenyl)propanoic acid (Compound
1059) using General Procedures 7 and 4 sequentially.
Compound 1061 was prepared from tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoate (INT-17) using General Procedures 10 then 8.
2-Bromo-5-(heptyloxy)pyridine was prepared from 6-bromopyridin-3-ol
and 1-bromoheptane using General Procedure 12.
Compound 1062 was prepared from tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoate (INT-17) and 2-bromo-5-(heptyloxy)pyridine using
General Procedures 10 then 8.
Compounds 1063-1066 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(5-(heptyloxy)pyrid-
in-2-yl)pyrimidin-2-yl)phenyl)propanoic acid (Compound 1062) using
General Procedures 7 then 8.
Compound 1067 was prepared from tert-butyl
(S)-3-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoate
tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoate (INT-17) using General Procedures 8, 7, 10 and 8
sequentially.
Compound 1068-1083 were prepared from (S)-tert-butyl
1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propano-
yl)pyrrolidine-2-carboxylate (INT-26) using General Procedures 7
then 8.
Compounds 1084-1087 were prepared from methyl
(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-
-2-carboxamido)propanoyl)pyrrolidine-3-carboxylate (INT-35) using
General Procedures 10 then 4.
(4-(4,4-dimethylcyclohexyl)phenyl)boronic acid was prepared from
4-(4,4-dimethylcyclohexyl)phenol using General Procedures 9 then
10.
Compound 1088 was prepared from tert-butyl
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylate (INT-38) and
(4-(4,4-dimethylcyclohexyl)phenyl)boronic acid using General
Procedures 10 then 8.
Compounds 1089-1093 were prepared from tert-butyl
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylate (INT-38) using General
Procedures 10 then 8.
Compounds 1094-1098 were prepared from methyl
(S)-1-((S)-2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)pro-
panoyl)pyrrolidine-3-carboxylate (INT-39) using General Procedures
7 then 4.
tert-butyl
(S)-1-(2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phen-
yl)propanoyl)azetidine-3-carboxylate (INT-53)
##STR00310##
Prepared using General Procedure 18. To a stirring solution of
tert-butyl
(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimi-
din-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (2.1 g, 3.0 mmol)
in THF (30 mL) was added Pd/C (0.32 g, 0.3 mmol) and the reaction
was flushed with hydrogen gas three times. The reaction mixture was
stirred under an atmosphere of hydrogen for 7 hours, filtered over
Celite, and concentrated. The crude tert-butyl
(S)-1-(2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propano-
yl)azetidine-3-carboxylate (INT-53) was used without further
purification. LCMS-ESI (m/z) calculated for
C.sub.34H.sub.44N.sub.4O.sub.4: 572.3; found 573.3 [M+H].sup.+,
t.sub.R=4.185 min (Method 16).
Compounds 1099-1122 were prepared from tert-butyl
(S)-1-(2-amino-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propano-
yl)azetidine-3-carboxylate (INT-53) using General Procedures 7 then
8.
(S)-tert-butyl
1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)-thiophene-2--
carboxamido)propanoyl)pyrrolidine-2-carboxylate (INT-54)
##STR00311##
Prepared using General Procedure 7. To a stirring solution of
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoic acid (1.0 g, 2.05 mmol), tert-butyl-L-prolinate
hydrochloride (468 mg, 2.25 mmol) and DIEA (2.14 mL, 12.3 mmol) in
DMF (4.0 mL) at 0.degree. C. was added HATU (856 mg, 2.25 mmol)
dissolved in DMF (1.5 mL), portion wise, over 10 minutes. The
reaction mixture was allowed to warm to room temperature and
stirred overnight. The crude material was diluted in DCM (100 mL),
washed with saturated aqueous bicarbonate (70 mL) and brine (70
mL). The organic layer was dried over MgSO.sub.4, filtered, and the
solvent removed under reduced pressure. The crude product was
purified by chromatography (EA/hexanes) to afford 1.06 g (80%) of
(S)-tert-butyl
1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)pyrrolidine-2-carboxylate (INT-54) as an off
white solid. LCMS-ESI (m/z) calculated for
C.sub.31H.sub.37BrN.sub.4O.sub.4S: 640.2; found 641.2 [M+H].sup.+,
t.sub.R=10.68 min (Method 14).
Compounds 1123-1127 were prepared from (S)-tert-butyl
1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)pyrrolidine-2-carboxylate (INT-54) using
General Procedures 10 then 8.
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoyl)-L-proline
##STR00312##
Prepared using General Procedure 8: To a stirred solution of
(S)-tert-butyl
1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)pyrrolidine-2-carboxylate (INT-54) (6.16 g,
9.60 mmol) in DCM (90 mL) was added TFA (10 mL). After 16 h,
solvents were evaporated and the residue purified by column
chromatography (DCM/iso-hexanes/EA/AcOH) to afford 3.38 g (60%) of
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-L-proline. LCMS-ESI (m/z) calculated for
C.sub.27H.sub.29 BrN.sub.4O.sub.4S: 584.1; found 585.2 [M+H].sup.+,
t.sub.R=2.49 min (Method 11).
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-ethyl-
cyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-proline
(Compound 1128)
##STR00313##
Prepared using General Procedure 10: To a stirred mixture of
(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-
-2-carboxamido)propanoyl)pyrrolidine-2-carboxylic acid (3.38 g,
5.77 mmol) and (4-((1r,4r)-4-ethylcyclohexyl)phenyl)boronic acid
(1.474 g, 6.35 mmol) in dioxane (40 mL) and water (40 mL) was added
NaHCO.sub.3 (0.97 g, 11.55 mmol). The mixture was de-gassed,
treated with PdCl.sub.2dppf (0.169 g, 0.231 mmol) then heated under
reflux for 3 h. The mixture was allowed to cool and extracted with
EA (2.times.50 mL). The combined organic layers were dried over
MgSO.sub.4 and solvents evaporated. Column chromatography
(iso-hexanes/EA) gave 1.7 g (44%) of
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-ethy-
lcyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-L-proline
(Compound 1128). LCMS-ESI (m/z) calculated for C.sub.41H.sub.48
N.sub.4O.sub.4S: 692.3; found 693.3 [M+H].sup.+, t.sub.R=11.09 min
(Method 10). The chiral purity was >95% e.e (Chiral Method).
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 12.51 (s, 1H), 9.18 (s, 2H),
8.74 (d, J=8.3 Hz, 1H), 8.33 (d, J=8.3 Hz, 2H), 7.80-7.74 (m, 2H),
7.71 (d, J=3.9 Hz, 1H), 7.53 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.4 Hz,
2H), 6.92 (d, J=3.9 Hz, 1H), 5.01-4.81 (m, 1H), 4.30 (dd, J=8.7,
4.3 Hz, 1H), 3.81-3.75 (m, 1H), 3.73-3.55 (m, 1H), 3.21-3.00 (m,
2H), 2.58-2.46 (m, 2H), 2.21-2.14 (m, 1H), 2.03-1.78 (m, 6H),
1.61-1.40 (m, 2H), 1.32-1.23 (m, 12H), 1.10-1.05 (m, 2H), 0.90 (t,
J=7.2 Hz, 3H).
tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4,4,5,5-
-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)phenyl)propanoyl)-D-al-
aninate (INT-56)
##STR00314##
Prepared using General Procedure 10. Into a solution of tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alaninate (1000 mg, 1.6 mmol) and
bis(pinacolato)diborane (620 mg, 2.4 mmol) in anhydrous dioxane (20
mL) was added potassium acetate (320 mg, 3.2 mmol). The solution
was degassed by N.sub.2 bubbling for 10 min before the addition of
PdCl.sub.2(dppf) (120 mg, 0.16 mmol). The mixture was heated in a
microwave reactor for 2 hr at 80.degree. C., then cooled, diluted
with DCM, washed with water, then dried and concentrated. The
resulting crude tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4,4,5,5-tetrameth-
yl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate
(INT-56) was used without further purification. LCMS-ESI (m/z)
calculated for C.sub.35H.sub.47BN.sub.4O.sub.6S: 662.6; found 663.3
[M+H].sup.+, t.sub.R=4.00 min. (Method 16).
Compounds 1129-1136 were prepared from tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4,4,5,5-tetrameth-
yl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate
(INT-56) using General Procedures 10 then 8.
tert-butyl
(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl-
)-thiophene-2-carboxamido)propanoyl)pyrrolidine-3-carboxylate
(INT-57)
##STR00315##
Prepared using General Procedure 7: To a stirring solution of
tert-butyl-(S)-pyrrolidine-3-carboxylate (2.52 g, 14.7 mmol) in DMF
(20 mL) were added DIEA (1.90 g, 14.7 mmol) and
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoic acid (6.00 mg, 12.3 mmol). The solution was
cooled to 0 and HATU (5.60 g, 2.88 mmol) was slowly added. The
reaction was stirred for 1 hour at 0.degree. C. and then warmed to
RT with stirring for 2 hours. The reaction solution was quenched
with aqueous NaHCO.sub.3 (10 mL) and water (20 mL) was added. The
half-white precipitate formed was filtered. The filtrate was
extracted with EA (3.times.30 mL) and the precipitate was dissolved
in this extract. The combined organic layers were washed with water
(2.times.100 mL), dried over MgSO.sub.4, and evaporated. The crude
compound was purified by column chromatography (EA/hexanes) to
afford 4.88 g (61%) of tert-butyl
(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-
-2-carboxamido)propanoyl)pyrrolidine-3-carboxylate (INT-57) as a
half-white powder. LCMS-ESI (m/z) calculated for
C.sub.31H.sub.37BrN.sub.4O.sub.4S: 641.6; found 642.4 [M+H].sup.+,
t.sub.R=3.95 min. (Method 16).
Compound 1137 was prepared from tert-butyl
(S)-1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-
-2-carboxamido)propanoyl)pyrrolidine-3-carboxylate (INT-57) using
General Procedures 10 then 8.
tert-butyl
(S)-3-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)-
propanoate
##STR00316##
Into a solution of tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1-
,3,2-dioxaborolan-2-yl)phenyl)propanoate (INT-16) (400 mg, 0.8
mmol) in isopropyl alcohol (5 mL) and water (5 mL) was added
CuBr.sub.2 (520 mg, 2.4 mmol). The mixture was heated at 70.degree.
C. for 15 hr, then diluted with Et.sub.2O and washed with saturated
NaCl. The organic layer was dried (Na.sub.2SO.sub.4) and purified
by chromatography (EA/hexanes) to provide 230 mg (63%) of
tert-butyl
(S)-3-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoate-
. LCMS-ESI (m/z) calculated for C.sub.22H.sub.28BrNO.sub.3S: 466.4;
found 410.0 [M-tBu].sup.+, t.sub.R=3.9 min. (Method 16).
(S)-3-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoic
acid
##STR00317##
Prepared using General Procedure 8. A solution of tert-butyl
(S)-3-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoate
(229 mg, 0.5 mmol) in DCM (5 ml) and TFA (5 mL) was stirred for 15
h at room temperature. The mixture was concentrated to remove the
solvents and the crude material was used without further
purification to provide 201 mg (100%) of
(S)-3-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoic
acid. LCMS-ESI (m/z) calculated for C.sub.18H.sub.20BrNO.sub.3S:
410.3; found 411.0 [M+H].sup.+, t.sub.R=2.07 min. (Method 16).
tert-butyl
((S)-3-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido-
)propanoyl)-D-alaninate (INT-58)
##STR00318##
Prepared using General Procedure 7. Into a solution of
(S)-3-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoic
acid (200 mg, 0.5 mmol), H-D-Ala-OtBu (178 mg, 1.0 mmol) and DIEA
(196 mg, 0.5 mmol) in DMF (5 ml) was added HATU (200 mg, 0.5 mmol).
After 2 h, the mixture was diluted with EA, washed with NaHCO.sub.3
and saturated NaCl, then purified by chromatography (EA/hexanes) to
provide 176 mg (66%) of tert-butyl
((S)-3-(4-bromophenyl)-2-(5-(tert-butyl)thiophene-2-carboxamido)propanoyl-
)-D-alaninate (INT-58). LCMS-ESI (m/z) calculated for
C.sub.25H.sub.33BrN.sub.2O.sub.4S: 536.1; found 537.1 [M+H].sup.+,
t.sub.R=3.69 min. (Method 16).
Tert-butyl
((S)-3-(4-(5-(4-bromophenyl)pyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiop-
hene-2-carboxamido)propanoyl)-D-alaninate (INT-59) was prepared
from tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4,4,5,5-tetrameth-
yl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate
(INT-56) and 1-bromo-4-iodobenzene using General Procedure 10.
Compound 1138 was prepared from tert-butyl
((S)-3-(4-(5-(4-bromophenyl)pyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiop-
hene-2-carboxamido)propanoyl)-D-alaninate (INT-59) using General
Procedures 10 then 8.
tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(3-fluor-
o-4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate
##STR00319##
Prepared using General Procedure 10. Into a solution of tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alaninate (150 mg, 0.24 mmol) in dioxane (4
mL) and water (2 mL) were added 3-fluoro-4-hydroxyphenyl boronic
acid (46 mg, 0.29 mmol), sodium carbonate decahydrate (140 mg, 0.48
mmol), and PdCl.sub.2(dppf) (36 mg, 0.05 mmol). The mixture was
heated at 70.degree. C. for 1 hr, then diluted with DCM and washed
with H.sub.2O. The resulting crude solution of tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(3-fluoro-4-hydrox-
yphenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate was used crude
in the next step. LCMS-ESI (m/z) calculated for
C.sub.35H.sub.39FN.sub.4O.sub.5S: 646.7; found 647.8 [M+H].sup.+,
t.sub.R=3.08 min. (Method 16).
tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(3-fluor-
o-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl-
)-D-alaninate (INT-60)
##STR00320##
Prepared using General Procedure 9. Into a solution of crude
tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(3-fluoro-4-hydrox-
yphenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate (150 mg, 0.2
mmol) in DCM (9 mL) at 0.degree. C. were added
N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (92 mg,
0.3 mmol) and DIEA (43 .mu.L, 0.2 mmol). After 4 h, the reaction
mixture was diluted with DCM, washed with 10% citric acid, then
dried and concentrated. Purification by chromatography (EA/hexanes)
provided 149 mg (78%) of tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(3-fluoro-4-(((tri-
fluoromethyl)
sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate
(INT-60). LCMS-ESI (m/z) calculated for
C.sub.36H.sub.38F.sub.4N.sub.4O.sub.7S.sub.2: 778.8; found 779.8
[M+H].sup.+, t.sub.R=4.01 min. (Method 16).
Compounds 1139-1141 were prepared from tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(3-fluoro-4-(((tri-
fluoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alanin-
ate (INT-60) using General Procedures 10 then 8.
tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(((tr-
ifluoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alani-
nate (INT-61)
##STR00321##
Prepared using General Procedure 9. To a stirring solution of
tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)p-
yrimidin-2-yl)phenyl)propanoyl)-D-alaninate (INT-36) (0.32 g, 0.50
mmol) and DIEA (0.11 mL, 0.63 mmol) in DCM (5 mL) at 0.degree. C.
was added
1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide
(0.22 g, 0.63 mmol). The reaction was stirred at room temperature
overnight and quenched with 10 mL 10% citric acid. The organic
layer was separated and washed with saturated sodium bicarbonate.
The crude material was purified by column chromatography
(EA/hexanes) to afford 0.24 g (63%) of tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(((trifluoromet-
hyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate
(INT-61) as a solid. LCMS-ESI (m/z) calculated for
C.sub.36H.sub.39F.sub.3N.sub.4O.sub.7S.sub.2: 760.2; found 760.8
[M+H].sup.+, t.sub.R=4.15 min (Method 16).
Compounds 1142-1145 were prepared from tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(((trifluoromet-
hyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate
(INT-61) using General Procedures 10, 18, then 8.
Compounds 1146-1151 were prepared from tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(((trifluoromet-
hyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate
(INT-61) using General Procedures 10 then 8.
tert-butyl
(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2--
yl)phenyl)propanoyl)azetidine-3-carboxylate
##STR00322##
Prepared using General Procedure 7. Into a DMF (10.0 mL) solution
of tert-butyl azetidine-3-carboxylate (6.79 g, 35.16 mmol) were
added DIEA (5.45 g, 42.18 mmol), and
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)pro-
panoic acid (3.21 g, 7.03 mmol). The solution was cooled to
-15.degree. C. and then HATU (8.27 g, 35.16 mmol) in 15 mL DMF
solution was slowly added. The reaction was stirred 1 hour at
-15.degree. C. and then warmed to RT with stirring for 2 hours. The
reaction solution was diluted with DCM (20 mL) and washed with
aqueous NaHCO.sub.3 (3.times.10 mL). The organic layer was
concentrated and purified by chromatography (EA/hexanes) to afford
3.2 g (76.6%) of tert-butyl
(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-
propanoyl)azetidine-3-carboxylate. LCMS-ESI (m/z) calculated for
C.sub.29H.sub.31BrN.sub.4O.sub.5: 594.2; found: 595.8 [M+H].sup.+:
t.sub.R=3.33 min (Method 16). .sup.1H NMR (400 MHz, DMSO) .delta.
9.06 (s, 2H), 8.27 (dd, J=8.2, 2.5 Hz, 2H), 7.74 (dd, J=7.9, 5.2
Hz, 1H), 7.41 (t, J=7.7 Hz, 2H), 7.28 (td, J=13.9, 6.9 Hz, 5H),
5.08-4.87 (m, 2H), 4.41-4.11 (m, 3H), 4.06-3.92 (m, 1H), 3.92-3.70
(m, 1.5H), 3.35 (dd, J=14.6, 5.6 Hz, 0.5H), 2.93 (dtd, J=23.1,
13.7, 7.7 Hz, 2H), 1.41 (s, 4H), 1.27 (s, 5H).
tert-butyl
1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-eth-
ylcyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylat-
e
##STR00323##
Prepared using General Procedure 10. To a stirring solution of
(4-((1r,4r)-4-ethylcyclohexyl)phenyl)boronic acid (3.43 g, 4.93
mmol) were added sodium carbonate decahydrate (0.89 g, 14.79 mmol),
tert-butyl
(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-
propanoyl)azetidine-3-carboxylate (2.93 g, 4.93 mmol),
Pd(dppf)Cl.sub.2 (36.0 mg, 0.049 mmol) in dioxane (18 mL) and
H.sub.2O (3.0 mL). The reaction mixture was degassed and heated to
80.degree. C. for 2 hours. The reaction mixture was dried under
reduced pressure and diluted with DCM (20 mL). The crude material
was extracted with aqueous NaHCO.sub.3 (3.times.20 mL). The
combined organics were dried over MgSO.sub.4 and concentrated. The
crude product was purified by chromatography (EA/hexane) to afford
2.71 g (78.3%) of tert-butyl
1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-ethylcyclohex-
yl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
as a solid. LCMS-ESI (m/z) calculated for
C.sub.43H.sub.50N.sub.4O.sub.5: 702.4; found 703.4 [M+H].sup.+,
t.sub.R=5.72 min (Method 16). .sup.1H NMR (400 MHz, DMSO) .delta.
9.20 (d, J=1.2 Hz, 2H), 8.49-8.09 (m, 2H), 7.77 (d, J=7.8 Hz, 3H),
7.41 (t, J=9.2 Hz, 4H), 7.28 (dt, J=13.7, 6.6 Hz, 5H), 5.06-4.91
(m, 2H), 4.39-4.21 (m, 2H), 4.16 (t, J=8.8 Hz, 0.5H), 3.99 (dd,
J=15.3, 9.3 Hz, 1H), 3.94-3.81 (m, 1H), 3.81-3.69 (m, 0.5H),
3.09-2.76 (m, 2H), 2.56 (d, J=12.1 Hz, 1H), 1.85 (d, J=10.6 Hz,
4H), 1.49 (dd, J=22.2, 12.5 Hz, 2H), 1.45-1.38 (m, 4H), 1.29 (d,
J=5.6 Hz, 5H), 1.27-1.19 (m, 4H), 1.06 (dd, J=21.9, 12.0 Hz, 2H),
0.90 (t, J=7.2 Hz, 3H).
tert-butyl
1-((S)-2-amino-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)pyr-
imidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (INT-62)
##STR00324##
Prepared using General Procedure 18. Into a solution of 1:1
MeOH/THF (40 mL) were added tert-butyl
1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1r,4r)-4-ethylcyclohex-
yl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
and Pd/C (100.0 mg, 10% Pd). The solution was degassed and stirred
under H.sub.2 at room temperature for 18 hours. The solution was
filtered through celite and then dried under vacuum to afford 2.1 g
(96.3%) of tert-butyl
1-((S)-2-amino-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)pyrimidin-2-y-
l)phenyl)propanoyl)azetidine-3-carboxylate (INT-62) as a solid
product. LCMS-ESI (m/z) calculated for
C.sub.35H.sub.44N.sub.4O.sub.3: 568.3; found: 569.4 [M+H].sup.+:
t.sub.R=4.43 min (Method 16). .sup.1H NMR (400 MHz, DMSO) .delta.
9.21 (d, J=2.7 Hz, 2H), 8.44 (d, J=8.2 Hz, 2H), 8.26 (s, 2H),
7.85-7.67 (m, 2H), 7.41 (dd, J=14.2, 5.7 Hz, 4H), 4.30-4.07 (m,
2H), 4.01 (t, J=9.4 Hz, 1H), 3.92 (dd, J=9.8, 6.2 Hz, 0.5H), 3.79
(dd, J=10.0, 6.4 Hz, 0.5H), 3.62 (t, J=9.0 Hz, 0.5H), 3.35 (d,
J=6.4 Hz, 1.5H), 3.23-3.11 (m, 1H), 3.07 (s, 1H), 3.01-2.91 (m,
1H), 2.63-2.52 (m, 1H), 1.86 (d, J=10.1 Hz, 4H), 1.49 (dd, J=22.3,
12.4 Hz, 2H), 1.40 (s, 4H), 1.33-1.19 (m, 3H), 1.16 (s, 4H),
1.14-0.99 (m, 2H), 0.90 (t, J=7.2 Hz, 3H). .sup.13C NMR (101 MHz,
DMSO) .delta. 170.98, 170.32, 167.33, 167.07, 161.54, 157.46,
155.01, 154.82, 148.23, 137.28, 136.14, 131.24, 130.95, 129.97,
129.82, 127.78, 127.73, 127.64, 126.64, 126.58, 81.04, 80.72,
52.24, 50.06, 49.79, 43.52, 38.33, 36.45, 33.62, 32.54, 32.07,
29.41, 27.53, 27.23, 11.31.
Compounds 1152-1170 and were prepared from tert-butyl
1-((S)-2-amino-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)pyrimidin-2-y-
l)phenyl)propanoyl)azetidine-3-carboxylate (INT-62) using General
Procedures 7 then 8.
tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluor-
o-4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate
##STR00325##
Prepared using General Procedure 10. Into a solution of tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alaninate (1200 mg, 1.9 mmol) in dioxane (10
mL) and water (3 mL) were added 2-fluoro-4-hydroxyphenyl boronic
acid (365 mg, 2.3 mmol), sodium carbonate decahydrate (1100 mg, 3.9
mmol), and PdCl.sub.2(dppf) (280 mg, 0.2 mmol). The mixture was
heated at 70.degree. C. for 1.5 hr, then diluted with DCM and
washed with H.sub.2O. The resulting crude solution of tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-hydrox-
yphenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate was used crude
in the next step. LCMS-ESI (m/z) calculated for
C.sub.35H.sub.39FN.sub.4O.sub.5S: 646.8; found 646.9 [M+H].sup.+,
t.sub.R=3.5 min. (Method 16).
tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluor-
o-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl-
)-D-alaninate (INT-63)
##STR00326##
Prepared using General Procedure 9. Into a solution of crude
tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-hydrox-
yphenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alaninate 1260 mg, 1.7
mmol) in DCM (10 mL) at 0.degree. C. were added
N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (775 mg,
2.2 mmol) and DIEA (360 .mu.L, 2.1 mmol). After 6 h, the reaction
mixture was diluted with DCM, washed with 10% citric acid, then
dried and concentrated. Purification by chromatography (EA/hexanes)
provided 1150 mg (89%) of tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-(((tri-
fluoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alanin-
ate (INT-63). LCMS-ESI (m/z) calculated for
C.sub.36H.sub.38F.sub.4N.sub.4O.sub.7S.sub.2: 778.8; found 779.8
[M+H].sup.+, t.sub.R=4.10 min. (Method 16).
Compounds 1171-1175 were prepared from tert-butyl
((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-(((tri-
fluoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)-D-alanin-
ate (INT-63) using General Procedures 10 then 8.
tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(((-
trifluoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetid-
ine-3-carboxylate (INT-65)
##STR00327##
Prepared using General Procedure 9. To a stirring solution of
tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl-
)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (INT-48)
(1.28 g, 2.0 mmol) and DIEA (0.45 mL, 2.5 mmol) in DCM (8 mL) at
0.degree. C. was added
1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfon-
amide (0.89 g, 2.5 mmol). The reaction was stirred at room
temperature overnight and quenched with 10 mL saturated sodium
bicarbonate. The aqueous layer was extracted with DCM (3.times.10
mL) and the combined organic layers were dried over magnesium
sulfate and concentrated. The crude material was purified by column
chromatography (EA/hexanes) to afford 1.4 g (91%) of tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(((trifluorom-
ethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carb-
oxylate (INT-65) as a solid. LCMS-ESI (m/z) calculated for
C.sub.37H.sub.39F.sub.3N.sub.4O.sub.7S: 772.2; found 772.7
[M+H].sup.+, t.sub.R=4.08 min (Method 16).
Compounds 1176-1187 were prepared from tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(((trifluorom-
ethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carb-
oxylate (INT-65) using General Procedures 10, 18, then 8.
tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-flu-
oro-4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylat-
e
##STR00328##
Prepared using General Procedure 10. Into a solution of tert-butyl
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylate (INT-38) (600 mg, 0.96
mmol) in dioxane (12 mL) and water (3 mL) were added
2-fluoro-4-hydroxyphenyl boronic acid (180 mg, 1.2 mmol), sodium
carbonate decahydrate (550 mg, 1.9 mmol), and PdCl.sub.2(dppf) (140
mg, 0.2 mmol). The mixture was heated at 65.degree. C. for 2 hr,
then diluted with DCM and washed with H.sub.2O. The resulting crude
solution of tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-hydr-
oxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
was used crude in the next step. LCMS-ESI (m/z) calculated for
C.sub.36H.sub.39FN.sub.4O.sub.5S: 658.8; found 659.9 [M+H].sup.+,
t.sub.R=3.49 min. (Method 16).
tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-flu-
oro-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propano-
yl)azetidine-3-carboxylate (INT-66)
##STR00329##
Prepared using General Procedure 9. Into a solution of crude
tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-hydr-
oxyphenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
(630 mg, 1.0 mmol) in DCM (12 mL) at 0.degree. C. were added
N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (375 mg,
1.1 mmol) and DIEA (200 .mu.L, 1.1 mmol). After 15 h, the reaction
mixture was diluted with DCM, washed with 10% citric acid, then
dried and concentrated. Purification by chromatography (EA/hexanes)
provided 622 mg (78%) of tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-(((t-
rifluoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidi-
ne-3-carboxylate (INT-66). LCMS-ESI (m/z) calculated for
C.sub.37H.sub.38F.sub.4N.sub.4O.sub.7S.sub.2: 790.9; found 791.8
[M+H].sup.+, t.sub.R=4.06 min. (Method 16).
Compounds 1188-1225 were prepared from tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-(((t-
rifluoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidi-
ne-3-carboxylate (INT-66) using General Procedures 10 then 8.
tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4'-bu-
tyl-3-fluoro-[1,1'-biphenyl]-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidin-
e-3-carboxylate
##STR00330##
Prepared using General Procedure 10. Into a solution of tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-(((t-
rifluoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidi-
ne-3-carboxylate (INT-66) (175 mg, 0.22 mmol) in dioxane (10 mL)
and water (3 mL) were added (4-butylphenyl)boronic acid (70 mg,
0.39 mmol), sodium carbonate, decahydrate (130 mg, 0.4 mmol), and
PdCl.sub.2(dppf) (32 mg, 0.04 mmol). The mixture was heated at
70.degree. C. for 2 hr, then diluted with DCM, washed with H.sub.2O
then purified by chromatography (EA/hexanes) to provide 145 mg
(85%) of tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4'-butyl-3-fluo-
ro-[1,1'-biphenyl]-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carbox-
ylate. LCMS-ESI (m/z) calculated for
C.sub.46H.sub.51FN.sub.4O.sub.4S: 774.5; found 775.8 [M-H].sup.+,
t.sub.R=5.48 min. (Method 16).
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4'-butyl-3-fluor-
o-[1,1'-biphenyl]-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxy-
lic acid (Compound 1226)
##STR00331##
Prepared using General Procedure 8. A solution of tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4'-butyl-3-fluo-
ro-[1,1'-biphenyl]-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carbox-
ylate (145 mg, 0.19 mmol) was dissolved in a 50% solution of
TFA/DCM (10 mL) for 2 hours. The volatile solvents were removed in
vacuo and the resulting crude material was dissolved in DCM (10 mL)
and concentrated three times. The resulting material was purified
by preparative HPLC to provide 120 mg (88%) of
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4'-butyl-3-fluo-
ro-[1,
1'-biphenyl]-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carbo-
xylic acid. LCMS-ESI (m/z) calculated for
C.sub.42H.sub.43FN.sub.4O.sub.4S: 718.9; found 719.8 [M+H].sup.+,
t.sub.R=9.33 min (Method 14). .sup.1H NMR (400 MHz, DMSO) .delta.
9.14 (s, 2H), 8.75 (d, J=8.1 Hz, 1H), 8.35 (dd, J=7.5, 4.7 Hz, 2H),
7.83 (t, J=8.2 Hz, 1H), 7.72 (m, 5H), 7.48 (d, J=8.1 Hz, 2H), 7.33
(d, J=7.8 Hz, 2H), 6.93 (d, J=3.7 Hz, 1H), 4.67 (m, 1H), 4.43 (t,
J=8.7 Hz, 1H), 4.36-4.25 (m, 1H), 4.18 (m, 1H), 4.11-3.95 (m, 1H),
3.97-3.80 (m, 1H), 3.51-3.38 (m, 0.5H), 3.39-3.26 (m, 0.5H), 3.10
(ddd, J=29.0, 18.4, 9.9 Hz, 2H), 2.64 (t, J=7.6 Hz, 2H), 1.67-1.52
(m, 2H), 1.43-1.24 (m, 11H), 0.92 (t, J=7.3 Hz, 3H).
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)-
-pyrimidin-2-yl)phenyl)propanoic acid
##STR00332##
Prepared using General Procedures 10 and 8: To a stirred mixture of
(S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)propano-
ate (INT-7) (20.17 g, 39.4 mmol) and
(4-((4-methylpentyl)oxy)phenyl)boronic acid (13.11 g, 59.0 mmol) in
dioxane (200 mL) was added NaHCO.sub.3 (87 mL of a 0.9 M aqueous
solution, 79 mmol). The mixture was warmed to 40.degree. C.,
de-gassed then treated with PdCl.sub.2dppf (0.720 g, 0.984 mmol)
and heated under reflux. After 3 h, the mixture was allowed to cool
then diluted with EA (400 mL) and washed successively with water
(2.times.300 mL) and brine (50 mL). The combined organic extracts
were dried over MgSO.sub.4 and solvents evaporated. The residue was
purified by column chromatography (iso-hexanes/EA) to give
intermediate ester as a white, waxy solid. This was taken into DCM
(200 mL) and stirred with TFA (20 mL). After 16 h, additional TFA
(20 mL) was charged. After a further 24 h, the mixture was diluted
with toluene (200 mL) and solvents evaporated. The residue was
re-slurried from iso-hexanes to afford 20.82 g (96%) of
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl-
)pyrimidin-2-yl)phenyl)propanoic acid. LCMS-ESI (m/z) calculated
for C.sub.33H.sub.35 N.sub.3O.sub.5: 553.3; found 554.1
[M+H].sup.+, t.sub.R=3.43 min (Method 6).
methyl
(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((4-methylpentyl)o-
xy)-phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
##STR00333##
Prepared using General Procedure 7: To a stirred solution of
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl-
)pyrimidin-2-yl)phenyl)propanoic acid (15 g, 27.1 mmol) and methyl
azetidine-3-carboxylate hydrochloride (12.32 g, 81 mmol) in DMF
(250 mL), at .about.5.degree. C., was added DIEA (25 mL, 135 mmol).
After 5 min, HATU (14.63 g, 38.5 mmol) was added in small portions
to maintain the internal temperature between 0 and -5.degree. C.
After 1 h, further DIEA (25 mL, 135 mmol) and amine (1 eq) were
charged. After 5 min, further HATU (11.33 g, 29.8 mmol) was added
in small portions. After 1 h the mixture was treated with water (20
mL) and stirred for 15 min. Further water was slowly added
(.about.80 mL) and the mixture stirred at .about.5.degree. C. for
30 min. The precipitate was collected by filtration, washing with
water (2.times.50 mL) and drying in the vacuum oven to afford 13.38
g (76%) of methyl
(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((4-methylpentyl)oxy)phe-
nyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate.
LCMS-ESI (m/z) calculated for C.sub.38H.sub.42 N.sub.4O.sub.6:
650.3; found 651.3 [M+H].sup.+, t.sub.R=9.46 min (Method 10).
methyl
(S)-1-(2-amino-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)pyrimidin-2-y-
l)phenyl)propanoyl)azetidine-3-carboxylate acetate
##STR00334##
Prepared using General Procedure 18: A stirred mixture of
(S)-methyl
1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)-
pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (13.38 g,
20.56 mmol) and 10% Pd/C (Johnson and Matthey Type 39 paste, 1.4 g)
in THF (150 mL) and acetic acid (1.8 mL, 30.8 mmol) was
hydrogenated under 3 bar. After 16 h, MeOH (100 mL) was added to
effect dissolution and the mixture further hydrogenated under 3
bar. After a further 3 h, the mixture was filtered through Celite
and solvents evaporated. The residue was re-slurried from EA (100
mL) to give 10.3 g (87%) of methyl
(S)-1-(2-amino-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)pyrimidin-2-yl)phen-
yl)propanoyl)azetidine-3-carboxylate acetate. LCMS-ESI (m/z)
calculated for C.sub.30H.sub.36N.sub.4O.sub.4: 516.3; found 517.2
[M+H].sup.+, t.sub.R=2.75 min (Method 11).
(S)-1-(2-amino-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)pyrimidin-2-yl)pheny-
l)-propanoyl)azetidine-3-carboxylic acid hydrochloride (INT-70)
##STR00335##
A stirred suspension of (S)-methyl
1-(2-amino-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)pyrimidin-2-yl)phenyl)p-
ropanoyl)azetidine-3-carboxylate acetate (4.5 g, 7.80 mmol) in
dioxane (35 mL) and water (18 mL) was treated with hydrogen
chloride (23.4 mL of a 10 M aqueous solution, 234 mmol). After 1 h,
further dioxane (20 mL) was added. After 24 h, the mixture was
diluted with water (50 mL) and brine (50 mL) and exhaustively
extracted with EA. The solvents were evaporated and the residue
further evaporated with toluene and dried in the vacuum oven to
afford 3.6 g (86%) of
(S)-1-(2-amino-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)pyrimidin-2-yl)phen-
yl)propanoyl)azetidine-3-carboxylic acid hydrochloride (INT-70).
LCMS-ESI (m/z) calculated for C.sub.29H.sub.34N.sub.4O.sub.4:
502.3; found 503.3 [M+H].sup.+, t.sub.R=5.32 min (Method 10).
Compounds 1227-1246 were prepared from
(S)-1-(2-amino-3-(4-(5-(4-((4-methylpentyl)oxy)phenyl)pyrimidin-2-yl)phen-
yl)propanoyl)azetidine-3-carboxylic acid hydrochloride (INT-70)
using General Procedure 3.
methyl
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophe-
ne-2-carboxamido)propanoyl)azetidine-3-carboxylate
##STR00336##
Prepared using General Procedure 7: To a stirred solution of
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoic acid (3.85 g, 7.90 mmol) in DMF (50 mL), treated
with methyl azetidine-3-carboxylate hydrochloride (3.59 g, 23.69
mmol) and cooled to -5.degree. C. whereupon DIEA (8.75 mL, 47.4
mmol) was added. When a clear solution was observed, HATU (7.51 g,
19.74 mmol) was added portionwise, to maintain internal temperature
between 0 and -5.degree. C. After 15 min, further HATU (0.75 g,
1.97 mmol) was charged. After a further 30 min the mixture was
quenched with water (2 mL) and allowed to warm to room temperature.
The mixture was diluted with water (.about.30 mL) and acidified
with AcOH. The precipitate was collected by filtration, washing
successively with water (3.times.30 mL) then ACN (2.times.5 mL) to
afford 4.25 g (92%) of methyl
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylate. LCMS-ESI (m/z)
calculated for C.sub.27H.sub.29BrN.sub.4O.sub.4S: 584.1; found
585.0 [M+H].sup.+, t.sub.R=2.55 min (Method 11).
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-ca-
rboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71)
##STR00337##
To a stirred mixture of water (140 mL) and AcOH (140 mL) was added
sulfuric acid (53.2 mL, 993 mmol) and the mixture allowed to cool
to room temperature. This was then added to a stirred solution of
(S)-methyl
1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carbo-
xamido)propanoyl)azetidine-3-carboxylate (19.39 g, 33.1 mmol) in
dioxane (225 mL). After 20 h, the mixture was diluted with ice
water (500 mL) and extracted with DCM (2.times.350 mL). The
combined organic extracts were washed with water (2.times.500 mL)
dried over MgSO.sub.4 and solvents evaporated. Column
chromatography (DCM/EA/AcOH) gave 12.96 g (69%) of
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71). LCMS-ESI
(m/z) calculated for C.sub.26H.sub.27BrN.sub.4O.sub.4S: 570.1;
found 571.0 [M+H].sup.+, t.sub.R=2.36 min (Method 11).
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoyl)-D-alanine (INT-72)
##STR00338##
Prepared using General Procedure 8: To a stirred solution of
(R)-tert-butyl
2-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanamido)propanoate (4.8 g, 7.80 mmol) in DCM (150
mL) was added TFA (18 mL). After 16 h, the reaction was diluted
with toluene (100 mL) and solvents evaporated to afford 4.36 g
(100%) of
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alanine (INT-72). LCMS-ESI (m/z) calculated
for C.sub.25H.sub.27BrN.sub.4O.sub.4S: 558.1; no m/z observed,
t.sub.R=2.43 min (Method 11).
Compounds 1247-1265 were prepared from
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alanine (INT-72) using General Procedure
10.
(E)-2-(2-(4-ethylphenyl)prop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxabor-
olane (INT-68)
##STR00339##
An oven-dried flask was charged with xantphos (222 mg, 0.38 mmol),
copper (I) chloride (38 mg, 0.38 mmol) and
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1073
mg, 4.22 mmol) then blanketed under nitrogen. THF (38 mL) was added
and the mixture stirred for 5 min. A solution of sodium
tert-butoxide (2.1 mL of a 2 M solution in THF, 4.2 mmol) was added
dropwise and the mixture stirred a further 5 min.
Ethyl-4-ethynylbenzene (538 .mu.L, 3.84 mmol) and iodomethane (956
.mu.L, 15.36 mmol) were charged and the flask sealed up with
parafilm. The mixture was allowed to stir for 16 h then diluted
with Et.sub.2O (100 mL) and washed with water (3.times.75 mL). The
organic layer was dried over Na.sub.2SO.sub.4 and solvents
evaporated to afford 0.2 g (19%) of
(E)-2-(2-(4-ethylphenyl)prop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolane (INT-68). LCMS-ESI (m/z) calculated for
C.sub.17H.sub.25BO.sub.2: 272.2; no m/z observed, t.sub.R=9.17 min
(Method 10). .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.34-7.29 (m,
2H), 7.09-7.06 (m, 2H), 5.51 (q, J=0.9 Hz, 1H), 2.48 (q, J=7.6 Hz,
2H), 2.21 (d, J=0.9 Hz, 3H), 1.13 (s, 12H), 1.06 (t, J=7.6 Hz,
3H).
Compound 1266 was prepared from
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alanine (INT-72) and
(E)-2-(2-(4-ethylphenyl)prop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolane (INT-68) using General Procedure 10.
Compounds 1267 and 1268 were prepared from
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alanine (INT-72) using General Procedure
11.
Compounds 1269 and 1270 were prepared from tert-butyl
(R)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)pro-
panoate using General Procedures 10, 18, 7, 8, 7 and 8
sequentially.
Compound 1271 was prepared from tert-butyl
(R)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)pro-
panoate using General Procedures 10, 8, 7, 18, 7 and 4
sequentially.
Compound 1272 was prepared from tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alaninate using General Procedure 36.
Compound 1273 was prepared from tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alaninate using General Procedures 11 and
8.
Compound 1274 was prepared from tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alaninate using General Procedures 10, 8 and
18 sequentially.
Compound 1275 was prepared from tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alaninate using General Procedures 21 and 8
sequentially.
Compound 1276 was prepared from tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alaninate using General Procedures 21 and
8.
Compound 1277 was prepared from tert-butyl
((S)-3-(4-(5-bromopyrimidin-2yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoyl)-D-alaninate using General Procedures 21, 8, and
18 sequentially.
Compounds 1278 and 1279 were prepared from methyl
1-((S)-2-amino-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)pyrimidin-2-y-
l)phenyl)propanoyl)azetidine-3-carboxylate using General Procedures
3 and 4 sequentially.
Compound 1280 was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 7, 8, and 8.
Compound 1281 was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)pheny-
l)pyrimidin-2-yl)phenyl)propanoic acid (Compound 192) using General
Procedures 7 then 8.
Compounds 1282-1320 were prepared from tert-butyl
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alaninate using General Procedures 10 then
8.
Compounds 1321 and 1322 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-ethyl-
cyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoic acid (Compound
1058) using General Procedures 7 then 4.
Compounds 1323-1328 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-ethyl-
cyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoic acid (Compound
1058) using General Procedures 7 then 8.
Compounds 1329-1332 were prepared from tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-(((t-
rifluoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidi-
ne-3-carboxylate (INT-66) using General Procedures 10 then 8.
Compound 1333 was prepared from 5-bromo-2-chloropyridine and
(4-((1r,4r)-4-ethylcyclohexyl)phenyl)boronic acid using General
Procedure 10 and then (S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)propanoate (INT-6) using General Procedures 10, 18,
7 and 8 sequentially.
Compound 1334 was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1r,4r)-4-ethyl-
cyclohexyl)phenyl)pyridin-2-yl)phenyl)propanoic acid (Compound
1333) using General Procedures 7 and 4 sequentially.
Compound 1335 was prepared from 2-bromo-5-chloropyridine and
(4-((1r,4r)-4-ethylcyclohexyl)phenyl)boronic acid using General
Procedure 10 and then (S)-tert-butyl
2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl)propanoate (INT-6) using General Procedures 10, 18,
7 and 8 sequentially.
1-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)ethan-1-one
##STR00340##
To a stirred solution of
1-bromo-4-((1r,4r)-4-ethylcyclohexyl)benzene (2.243 g, 8.39 mmol)
in THF (20 mL) at -78.degree. C. was added butyllithium (3.69 mL of
a 2.5 M solution in hexanes, 9.23 mmol). After 40 min,
1-morpholinoethanone (1.0 mL, 9.23 mmol) was added dropwise. After
1 h the mixture was warmed to 0.degree. C. After a further 1 h, the
mixture was quenched into NH.sub.4Cl (50 mL) and extracted with
diethyl ether (3.times.30 mL). The combined organic extracts were
dried over MgSO.sub.4 and solvents evaporated. The residue was
stirred in iso-hexanes (10 mL) and filtered and the liquors
evaporated. The resulting residue was purified by column
chromatography (iso-hexanes/diethyl ether) to afford 687 mg (36%)
of 1-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)ethan-1-one. LCMS-ESI
(m/z) calculated for C.sub.16H.sub.22O: 230.2; no m/z observed,
t.sub.R=2.59 min (Method 6).
2-bromo-1-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)ethan-1-one
##STR00341##
A stirred solution of
1-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)ethan-1-one (685 mg, 2.97
mmol) in DCM (40 mL) was treated with trimethylphenylammonium
tribromide (1230 mg, 3.27 mmol). After 16 h, the mixture was washed
with NaHCO.sub.3 (50 mL), dried over Na.sub.2SO.sub.4 and solvents
evaporated to afford 920 mg (100%) of
2-bromo-1-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)ethan-1-one.
LCMS-ESI (m/z) calculated for C.sub.16H.sub.21BrO: 308.1; found
309.1 [M+H].sup.+, t.sub.R=9.01 min (Method 10).
3-(4-bromophenyl)-6-(4-((1s,4s)-4-ethylcyclohexyl)phenyl)-1,2,4-triazine
##STR00342##
To a stirred solution of
2-bromo-1-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)ethan-1-one (417 mg,
1.35 mmol) and 4-bromobenzohydrazide (580 mg, 2.7 mmol) in EtOH (7
mL) and AcOH (3 mL) was added potassium acetate (159 mg, 1.62 mmol)
and the resulting mixture heated under reflux. After 4 h, the
mixture was allowed to cool then diluted with THF (50 mL) and
silica (2 g) and solvents evaporated. Column chromatography
(EA/DCM) gave a solid that was re-slurried from MeOH to afford 240
mg (42%) of
3-(4-bromophenyl)-6-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)-1,2,4-triazine
as bright yellow needles. LCMS-ESI (m/z) calculated for
C.sub.23H.sub.24BrN.sub.3: 421.1; found 422.1 [M+H].sup.+,
t.sub.R=11.88 min (Method 10).
Compound 1336 was prepared from
3-(4-bromophenyl)-6-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)-1,2,4-triazine
and (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate
using General Procedures 31, 8, 7 and 4 sequentially.
Compound 1337 was prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(6-(4-((1r,4r)-4-ethyl-
cyclohexyl)phenyl)-1,2,4-triazin-3-yl)phenyl)propanoic acid
(Compound 1336) using General Procedures 7 and 4 sequentially.
Compound 1338 was prepared from
((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-car-
boxamido)propanoyl)-D-alanine (INT-72) using General Procedure
37.
Compound 1339 was prepared from methyl
1-((S)-2-amino-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)pyrimidin-2-y-
l)phenyl)propanoyl)azetidine-3-carboxylate and
5-(2-cyanopropan-2-yl)thiophene-2-carboxylic acid using General
Procedures 7 and 4 sequentially.
1-(thiophen-2-yl)cyclopropanecarbonitrile
##STR00343##
To a stirring solution of 2-(thiophen-2-yl)acetonitrile (1.1 mL, 10
mmol) in DMSO (40 mL) was added sodium hydride (1 g of a 60%
dispersion in mineral oil, 25.00 mmol). After 30 min,
1,2-dibromoethane (1.7 mL, 20.00 mmol) was added dropwise, and the
mixture was stirred for 2 h. The reaction was quenched by the
addition of water (100 mL) and extracted with diethyl ether
(3.times.100 mL). The combined organic extracts were dried over
MgSO.sub.4 and solvents evaporated. Column chromatography
(EA/iso-hexanes) gave 0.8 g (54%) of
1-(thiophen-2-yl)cyclopropanecarbonitrile. LCMS-ESI (m/z)
calculated for C.sub.8H.sub.7NS: 149.0; found 150.3 [M+H].sup.+,
t.sub.R=1.88 min (Method 11).
1-(5-formylthiophen-2-yl)cyclopropanecarbonitrile
##STR00344##
To a stirring solution of 1-(thiophen-2-yl)cyclopropanecarbonitrile
(800 mg, 5.36 mmol) in THF (30 mL) at -78.degree. C. was added
butylithium (2.7 mL of a 2.5 M solution in hexanes, 6.70 mmol).
After 1 h, DMF (1.6 mL, 21.45 mmol) was added. The reaction mixture
was stirred for 6 h at -78.degree. C. and then quenched by the
addition of saturated aqueous NH.sub.4Cl (25 mL). The mixture was
extracted with EA (3.times.25 mL) and the combined organic extracts
washed with brine (20 mL), dried over MgSO.sub.4 and solvents
evaporated. Column chromatography (EA/iso-hexanes) gave 111 mg
(12%) of 1-(5-formylthiophen-2-yl)cyclopropanecarbonitrile.
LCMS-ESI (m/z) calculated for C.sub.9H.sub.7NOS: 177.0; found 178.3
[M+H].sup.+, t.sub.R=1.52 min (Method 10).
5-(1-cyanocyclopropyl)thiophene-2-carboxylic acid
##STR00345##
To a stirring solution of
1-(5-formylthiophen-2-yl)cyclopropanecarbonitrile (200 mg, 1.13
mmol) and 2,3-dimethylbut-2-ene (6.77 mL, 6.77 mmol) in
tert-butanol (3 mL) was added a solution of NaClO.sub.2 (765 mg,
6.77 mmol) and NaH.sub.2PO.sub.4 (812 mg, 6.77 mmol) in water (12
mL). After 30 min, the volatiles were evaporated and the residue
treated with 1 M HCl (50 mL) then extracted with EA (3.times.25
mL). The combined organic extracts were washed with brine (50 mL),
dried over MgSO.sub.4, and sovents evaporated to afford 180 mg
(83%) of 5-(1-cyanocyclopropyl)thiophene-2-carboxylic acid.
LCMS-ESI (m/z) calculated for C.sub.9H.sub.7NOS: 193.0; found 194.1
[M+H].sup.+, t.sub.R=1.37 min (Method 11).
Compound 1340 was prepared from methyl
1-((S)-2-amino-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)pyrimidin-2-y-
l)phenyl)propanoyl)azetidine-3-carboxylate and
5-(1-cyanocyclopropyl)thiophene-2-carboxylic acid using General
Procedures 7 and 4 sequentially.
Compound 1341 was prepared from
(4-((1r,4r)-4-ethylcyclohexyl)phenyl)boronic acid and
5-bromo-2-iodopyridine using General Procedure 10 and then using
(S)-tert-butyl
2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1,3,2-
-dioxaborolan-2-yl)phenyl)propanoate tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(4,4,5,5-tetramethyl-1-
,3,2-dioxaborolan-2-yl)phenyl)propanoate (INT-16) and General
Procedures 10, 8, 7 and 4 sequentially.
Compound 1342 was prepared from tert-butyl
1-((S)-2-amino-3-(4-(5-(4-((1r,4r)-4-ethylcyclohexyl)phenyl)pyrimidin-2-y-
l)phenyl)propanoyl)azetidine-3-carboxylate (INT-62) using General
Procedures 7 then 8.
1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1s,4r)-4-pro-
pylcyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxyli-
c acid (Compound 1343)
##STR00346##
Prepared using General Procedure 10: To a stirring solution of
sodium bicarbonate (1.764 g, 21.00 mmol) in water, was added a
solution of (4-((1s,4r)-4-propylcyclohexyl)phenyl)boronic acid
(2.240 g, 9.10 mmol) and
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-
-2-carboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) (4 g,
7.00 mmol) in dioxane (100 mL). The mixture was warmed to
40.degree. C., de-gassed, then treated with PdCl.sub.2dppf (0.256
g, 0.350 mmol). The reaction was heated under reflux. After 2 h,
the mixture was allowed to cool, treated with 1 M HCl (300 mL) and
extracted with EA (2.times.300 mL). The combined organic extracts
were dried over MgSO.sub.4 and solvents evaporated. Column
chromatography (AcOH/EA/iso-hexanes) gave 2.93 g (60%) of
1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1s,4r)-4-pr-
opylcyclohexyl)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxyl-
ic acid. LCMS-ESI (m/z) calculated for
C.sub.41H.sub.48N.sub.4O.sub.4S: 692.3; no m/z observed,
t.sub.R=11.04 min (Method 10). Chiral analysis (Chiral Method 1)
showed >95% single peak. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.73 (s, 1H), 9.18 (d, J=1.9 Hz, 2H), 8.75 (dd, J=8.2, 2.6
Hz, 1H), 8.49-8.19 (m, 2H), 7.80-7.73 (m, 2H), 7.70 (d, J=3.9 Hz,
1H), 7.51-7.43 (m, 2H), 7.43-7.36 (m, 2H), 6.93 (dd, J=3.9, 1.4 Hz,
1H), 4.70-4.64 (m, 1H), 4.43 (t, J=8.0 Hz, 0.5H), 4.32-4.28 (m,
0.5H), 4.26-4.12 (m, 1H), 4.08-3.99 (m, 1H), 3.93-3.86 (m, 1H),
3.47-3.40 (m, 0.5H), 3.37-3.29 (m, 0.5H), 3.19-2.95 (m, 2H),
2.57-2.51 (m, 1H), 1.84 (d, J=11.6 Hz, 4H), 1.58-1.41 (m, 2H),
1.39-1.30 (m, 12H), 1.29-1.15 (m, 2H), 1.10-1.02 (m, 2H), 0.89 (t,
J=7.2 Hz, 3H).
Compounds 1344-1354 were prepared from tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoate (INT-17) using General Procedures 10 then 8.
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4'-(trifluoromethyl-
)-[1,1'-biphenyl]-4-yl)pyrimidin-2-yl)phenyl)propanoic acid
(Compound 1355)
##STR00347##
Prepared using General Procedure 10: To a stirring solution of
NaHCO.sub.3 (2.52 g, 30.0 mmol) in water (40 mL), was added a
solution of (4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)boronic acid
(3.46 g, 12.99 mmol) and
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thioph-
ene-2-carboxamido)propanoic acid (4.88 g, 9.99 mmol) in dioxane
(100 mL). The mixture was warmed to 40.degree. C., de-gassed, and
treated with PdCl.sub.2dppf (0.366 g, 0.500 mmol). The mixture was
heated under reflux for 3 h whereupon further PdCl.sub.2dppf (0.183
g, 0.25 mmol) and (4'-(trifluoromethyl)-[1,1'biphenyl]-4-yl)boronic
acid (1.73 g, 6 mmol) were added. After a further 3 h, the mixture
was allowed to cool, treated with 1 M HCl (100 mL) and extracted
with EA (2.times.200 mL) then DCM (200 mL). The combined organic
extracts were dried over MgSO.sub.4 and solvents evaporated. Column
chromatography (AcOH/EA/DCM/iso-hexanes) followed by re-slurry from
ACN (200 mL) gave 3.555 (57%) of
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4'-(trifluoromethy-
l)-[1,1'-biphenyl]-4-yl)pyrimidin-2-yl)phenyl)propanoic acid
(Compound 1355). LCMS-ESI (m/z) calculated for
C.sub.35H.sub.30F.sub.3N.sub.3O.sub.3S: 629.2; no m/z observed,
t.sub.R=9.69 min (Method 10). Chiral analysis (Chiral Method 1)
showed >95% single peak. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.85 (s, 1H), 9.30 (s, 2H), 8.67 (d, J=8.3 Hz, 1H),
8.44-8.32 (m, 2H), 8.10-7.97 (m, 4H), 7.97-7.91 (m, 2H), 7.86 (d,
J=8.2 Hz, 2H), 7.65 (d, J=3.8 Hz, 1H), 7.54-7.43 (m, 2H), 6.93 (d,
J=3.9 Hz, 1H), 4.66 (ddd, J=10.5, 8.3, 4.5 Hz, 1H), 3.28 (dd,
J=13.9, 4.5 Hz, 1H), 3.14 (dd, J=13.9, 10.5 Hz, 1H), 1.33 (s,
9H).
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4'-(trifluoromethox-
y)-[1,1'-biphenyl]-4-yl)pyrimidin-2-yl)phenyl)propanoic acid
(Compound 1356)
##STR00348##
Prepared using General Procedure 10: To a stirring solution of
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoic acid (5.4 g, 11.06 mmol) and
(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)boronic acid (3.20 g,
11.35 mmol) in 1,4-dioxane (150 mL) was added NaHCO.sub.3 (36.9 mL
of a 0.9 M aqueous solution, 33.2 mmol). The mixture was heated to
40.degree. C. and degassed, then treated with PdCl.sub.2dppf (0.243
g, 0.332 mmol). The reaction was heated under reflux for 5 h
whereupon further PdCl.sub.2dppf (0.243 g, 0.332 mmol) and
(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)boronic acid (1.80 g,
6.38 mmol) were charged. After a further 1 h, the mixture was
allowed to cool then quenched into 1 M HCl (75 mL) and extracted
with EA (2.times.200 mL). The combined organics were evaporated and
the residue purified by column chromatography
(AcOH/EA/DCM/iso-hexanes) and re-slurry from ACN (125 mL) to afford
3.6 g (50%) of
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4'-(trifluorometho-
xy)-[1,1'-biphenyl]-4-yl)pyrimidin-2-yl)phenyl)propanoic acid
(Compound 1356). LCMS-ESI (m/z) calculated for
C.sub.35H.sub.30F.sub.3N.sub.3O.sub.4S: 645.2; found 646.2
[M+H].sup.+, t.sub.R=9.88 min (Method 10). Chiral analysis (Chiral
Method 1) showed >95% single peak. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.85 (s, 1H), 9.29 (s, 2H), 8.66 (d, J=8.3
Hz, 1H), 8.44-8.29 (m, 2H), 8.04-7.96 (m, 2H), 7.93-7.83 (m, 4H),
7.65 (d, J=3.9 Hz, 1H), 7.55-7.44 (m, 4H), 6.93 (d, J=3.9 Hz, 1H),
4.66 (ddd, J=10.5, 8.3, 4.5 Hz, 1H), 3.28 (dd, J=13.9, 4.5 Hz, 1H),
3.14 (dd, J=13.9, 10.6 Hz, 1H), 1.32 (s, 9H).
Compounds 1357, 1358, and 1393 were prepared from tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-hydroxyphenyl)py-
rimidin-2-yl)phenyl)propanoate using General Procedures 9, 10 and 8
sequentially.
tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-
-4-hydroxyphenyl)pyrimidin-2-yl)phenyl)propanoate
##STR00349##
Prepared using General Procedure 10: To a stirring solution of
tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoate (INT-17) (0.75 g, 1.4 mmol) and
(2-fluoro-4-hydroxyphenyl) boronic acid (0.26 g, 1.65 mmol) in 4:1
dioxane: H.sub.2O (12 mL) was added sodium carbonate, decahydrate
(0.80 g, 2.8 mmol). The reaction mixture was degassed with nitrogen
bubbling and then PdCl.sub.2(dppf) (0.14 g, 0.2 mmol) was added and
the reaction mixture was heated for 1 h at 65.degree. C. The
mixture was cooled, diluted with DCM and washed with 10% citric
acid. The organic extract was dried over Na.sub.2SO.sub.4 and
concentrated to afford 0.79 g (.about.100%) of crude tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-hydroxy-
phenyl)pyrimidin-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated
for C.sub.32H.sub.34FN.sub.3O.sub.4S: 575.7; found 576.2
[M+Na].sup.+, t.sub.R=3.6 min (Method 25).
tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-
-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoate
(INT-76)
##STR00350##
Prepared using General Procedure 9: To a stirring solution of crude
tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-hydroxy-
phenyl)pyrimidin-2-yl)phenyl)propanoate (0.79 g, 1.4 mmol) and DIEA
(0.29 mL, 1.5 mmol) in DCM (10 mL) at 0.degree. C. was added
1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide
(0.54 g, 1.6 mmol). The reaction mixture was allowed to warm to
room temperature and stirred overnight. The reaction mixture was
diluted with DCM (200 mL) and washed with 10% citric acid
(3.times.200 mL). The combined organic extracts were dried over
Na.sub.2SO.sub.4, concentrated and purified by column
chromatography (EA/hexane) to afford 0.75 g (76%) tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-(((trif-
luoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoate
(INT-76). LCMS-ESI (m/z) calculated for
C.sub.33H.sub.33F.sub.4N.sub.3O.sub.6S.sub.2: 707.2; found 652.1
[M-tBu].sup.+, t.sub.R=4.5 min (Method 25).
Compounds 1359-1365 were prepared from tert-butyl
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-(((trif-
luoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoate
(INT-76) using General Procedures 10 then 8.
tert-butyl
(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(3-fluoro-4'-prop-
yl-[1,1'-biphenyl]-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carbox-
ylate
##STR00351##
Prepared using General Procedure 10: To a stirring solution of
tert-butyl
(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-
propanoyl)azetidine-3-carboxylate (300 mg, 0.5 mmol) and
2-(3-fluoro-4'-propyl-[1,1'-biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dio-
xaborolane (206 mg, 0.61 mmol) in 3:1 dioxanes: H.sub.2O (10 mL)
was added sodium carbonate, decahydrate (290 mg, 1.01 mmol). The
mixture was degassed using nitrogen bubbling and then
PdCl.sub.2(dppf) (74 mg, 0.1 mmol) was added and the mixture was
heated at 65.degree. C. After 18 h, the reaction mixture was
diluted with DCM and washed with brine. The organic layer was dried
(Na.sub.2SO.sub.4) and purified by column chromatography (EA/hex)
to provide 270 mg (74%) of tert-butyl
(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(3-fluoro-4'-propyl-[1,1'-b-
iphenyl]-4-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate.
LCMS-ESI (m/z) calculated for C.sub.43H.sub.54N.sub.4O.sub.5:
706.9; found 707.4 [M+H].sup.+, t.sub.R=5.3 min (Method 25).
tert-butyl
(S)-1-(2-amino-3-(4-(5-(3-fluoro-4'-propyl-[1,1'-biphenyl]-4-yl-
)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
(INT-77)
##STR00352##
Prepared using General Procedure 18: To a stirring solution of
tert-butyl
(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(3-fluoro-4'-propyl-[1,
1'-biphenyl]-4-yl)pyrimidin-2yl)phenyl)propanoyl)azetidine-3-carboxylate
(80 mg, 0.11 mmol) in EA (4 mL) was added Pd/C (19 mg, 0.02 mmol)
and the reaction was flushed with hydrogen three times. The
reaction mixture was stirred under an atmosphere of hydrogen for 24
hours, the mixture was filtered through Celite, and concentrated to
give 90 mg (138%) of tert-butyl
(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-
propanoyl)azetidine-3-carboxylate (INT-77), contaminated with
residual Pd/C. LCMS-ESI (m/z) calculated for
C.sub.36H.sub.39FN.sub.4O.sub.3: 594.7 found 595.3 [M+H].sup.+,
t.sub.R=3.8 min (Method 25).
Compounds 1366-1391 were prepared from tert-butyl
(S)-2-amino-3-(4-(5-(4-((1s,4s)-4-ethylcyclohexyl)phenyl)pyrimidin-2-yl)p-
henyl)propanoate (INT-78) using General Procedures 7 then 8.
Compound 1392 was prepared from (R)-tert-butyl
3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxam-
ido)propanoate (R)-INT-17 using General Procedures 10 and 8
sequentially.
Compounds 1394 and 1395 were prepared from tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(((trifluorom-
ethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carb-
oxylate (INT-65) using General Procedures 10 then 8.
Compound 1396 was prepared from tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-(((t-
rifluoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidi-
ne-3-carboxylate tert-butyl
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(2-fluoro-4-(((t-
rifluoromethyl)sulfonyl)oxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidi-
ne-3-carboxylate (INT-66) using General Procedures 10 and 8
sequentially.
Compounds 1397-1410 were prepared from tert-butyl
(S)-1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-
propanoyl)azetidine-3-carboxylate (INT-77) using General Procedures
7 then 8.
4-(4-propylcyclohexyl)piperazin-2-one was prepared from
4-propylcyclohexanone and piperazin-2-one using General Procedure
15.
Compounds 1411 and 1420 were prepared from 4-(4-propylcyclohexyl)
piperazin-2-one and
(rac)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-
-carboxamido)propanoyl)azetidine-3-carboxylic acid (racemic-INT-71)
using General Procedure 11.
1-benzyl-4-(4-butylphenyl)piperidin-4-ol
##STR00353##
To a stirring solution of 1-bromo-4-butylbenzene (3.72 g, 17.44
mmol) in THF (50 mL) at -78.degree. C. was added butyllithium (7.61
mL of a 2.5 M solution in hexanes, 19.02 mmol). After 1 h,
1-benzylpiperidin-4-one (2.94 mL, 15.85 mmol) was added. The
reaction was stirred at -78.degree. C. for 1 h, then warmed to room
temperature and stirred for a further 1 h. The reaction was
quenched with ammonium chloride (30 mL of a saturated aqueous
solution) and extracted with EA (3.times.30 mL). The combined
organic extracts were washed with brine (30 mL), dried over
MgSO.sub.4 and solvents evaporated to afford 3.5 g (68%) of
1-benzyl-4-(4-butylphenyl)piperidin-4-ol. LCMS-ESI (m/z) calculated
for C.sub.22H.sub.29NO: 323.2; found 324.3 [M+H].sup.+,
t.sub.R=1.51 min (Method 11).
1-benzyl-4-(4-butylphenyl)-1,2,3,6-tetrahydropyridine
##STR00354##
Prepared using General Procedure 39: To a stirring solution of
1-benzyl-4-(4-butylphenyl)piperidin-4-ol (3.5 g, 10.82 mmol) in DCM
(15 mL) was added TFA (15 mL). After 3.5 h, solvents were
evaporated and the residue taken into EA (50 mL) and washed with
NaHCO.sub.3 (50 mL). The aqueous was further extracted with EA (50
mL) and the combined organic extracts dried over MgSO.sub.4 and
solvents evaporated to afford 3.3 g (100%) of
1-benzyl-4-(4-butylphenyl)-1,2,3,6-tetrahydropyridine. LCMS-ESI
(m/z) calculated for C.sub.22H.sub.27N: 305.2; found 306.2
[M+H].sup.+, t.sub.R=1.65 min (Method 11).
4-(4-butylphenyl)piperidine
##STR00355##
Prepared using General Procedure 18: To a stirring solution of
1-benzyl-4-(4-butylphenyl)-1,2,3,6-tetrahydropyridine (3.27 g,
10.71 mmol) in MeOH (30 mL) was added ammonium formate (2.025 g,
32.1 mmol). After complete dissolution, 10% Pd on carbon (Johnson
and Matthey type 39 paste, 1.2 g) was added and the reaction
mixture heated under reflux. After 16 h, the reaction mixture was
allowed to cool and filtered through a glass microfibre filter,
washing with MeOH. Solvents were evaporated and the resiude taken
into ether (50 mL) and washed with NaHCO3 (50 mL). The aqueous was
further extracted with ether (50 mL) and the combined organic
extracts dried over MgSO.sub.4 and solvents evaporated to afford 2
g (86%) of 4-(4-butylphenyl)piperidine as a yellow solid. LCMS-ESI
(m/z) calculated for C.sub.22H.sub.27N: 217.4; found 218.2
[M+H].sup.+, t.sub.R=3.09 min (Method 10).
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(4-butylphenyl-
)-piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic
acid (Compound 1412)
##STR00356##
To a stirring solution of
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) (504 mg,
0.882 mmol) and 4-(4-butylphenyl)piperidine (249 mg, 1.146 mmol) in
toluene (12 mL) was added sodium tert-butoxide (339 mg, 3.53 mmol),
BINAP (54.9 mg, 0.088 mmol) and Pd.sub.2(dba).sub.3 (40.4 mg, 0.044
mmol). The resulting reaction mixture was degassed at 40.degree.
C., before being heated at 100.degree. C. for 16 h. The mixture was
allowed to cool and quenched with 1 M HCl (5 mL) then extracted
with EA (3.times.10 mL). The combined organic extracts were washed
with brine (10 mL), dried over MgSO.sub.4 and solvents evaporated.
Column chromatography (EA/AcOH/DCM/iso-hexanes) then re-slurry from
ACN gave 180 mg (29%) of
(S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(4-butylpheny-
l)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic
acid (Compound 1412) as a cream solid. LCMS-ESI (m/z) calculated
for C.sub.41H.sub.49N.sub.5O.sub.4S: 707.4; found 708.3
[M+H].sup.+, t.sub.R=3.12 min (Method 11). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.73 (s, 1H), 8.72 (app dd, J=8.2, 3.8 Hz,
1H), 8.61 (app d, J=1.9 Hz, 2H), 8.16 (app dd, J=8.2, 6.0 Hz, 2H),
7.70 (app dd, J=3.8, 1.2 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.25-7.06
(m, 4H), 6.93 (app dd, J=3.9, 1.8 Hz, 1H), 4.64 (p, J=8.2, 7.7 Hz,
1H), 4.46-4.41 (m, 0.5H), 4.31-4.29 (m, 0.5H), 4.23-4.11 (m, 1H),
4.11-3.71 (m, 4H), 3.48-3.42 (m, 0.5H), 3.35-3.29 (m, 0.5H),
3.14-2.81 (m, 4H), 2.74-2.10 (m, 1H), 2.56-2.52 (m, 2H), 1.99-1.62
(m, 4H), 1.64-1.40 (m, 2H), 1.32 (m, 11H), 0.90 (t, J=7.3 Hz,
3H).
(1s,4r)-methyl 4-propylcyclohexanecarboxylate
##STR00357##
Prepared using General Procedure 22: To stirring methanol (1.2 L)
was added trimethylsilyl chloride (75 mL, 591 mmol). After 10 min
(1s,4r)-4-propylcyclohexanecarboxylic acid (102 g, 599 mmol) was
added and the mixture heated under reflux for 3.5 h. The mixture
was allowed to cool, solvents evaporated, and azeotroped with
toluene (2.times.300 mL). The residue was taken into DCM (200 mL)
and stirred with saturated aqueous sodium bicarbonate (200 mL) for
2 h. The layers were separated and the organics dried over
MgSO.sub.4 and solvents evaporated to afford 109 g (99%) of
(1s,4r)-methyl 4-propylcyclohexanecarboxylate (109 g, 586 mmol, 98%
yield) as a colourless oil. LCMS-ESI (m/z) calculated for
C.sub.11H.sub.20O.sub.2: 184.2; no UV or m/z observed. .sup.1H NMR
(400 MHz, Chloroform-d) .delta. 3.68 (s, 3H), 2.24 (tt, J=12.3, 3.6
Hz, 1H), 2.06-1.91 (m, 2H), 1.91-1.73 (m, 2H), 1.50-1.37 (m, 2H),
1.37-1.28 (m, 2H), 1.28-1.14 (m, 3H), 0.99-0.82 (m, 5H).
4-((1s,4r)-4-propylcyclohexyl)hepta-1,6-dien-4-ol
##STR00358##
To a stirring solution of (1s,4r)-methyl
4-propylcyclohexanecarboxylate (33.5 g, 182 mmol) in THF (450 mL)
at -10.degree. C. was added allylmagnesium chloride in THF (200 mL
of a 2 M solution in THF, 400 mmol) such that the internal
temperature was maintained below 0.degree. C. The mixture was
allowed to warm slowly. After 16 h, the mixture was quenched with
ammonium chloride (200 mL of a saturated aqueous solution) then
treated with water (100 mL) and the layers were separated. The
aqueous layer was further extracted with Et.sub.2O (2.times.350 mL)
and the combined organic extracts dried over MgSO.sub.4 and
solvents evaporated to afford 42.3 g (98%) of
4-((1s,4r)-4-propylcyclohexyl)hepta-1,6-dien-4-ol (42.3 g, 161
mmol, 89% yield) as a yellow oil. LCMS-ESI (m/z) calculated for
C.sub.16H.sub.28O: 236.2; no UV or m/z observed. .sup.1H NMR (400
MHz, Chloroform-d) .delta. 6.01-5.76 (m, 2H), 5.23-5.02 (m, 4H),
2.41-2.10 (m, 4H), 1.87-1.75 (m, 4H), 1.47-1.27 (m, 3H), 1.25-1.05
(m, 5H), 0.96-0.81 (m, 5H).
1-benzyl-4-((1s,4r)-4-propylcyclohexyl)piperidin-4-ol
##STR00359##
A stirring solution of
4-((1s,4r)-4-propylcyclohexyl)hepta-1,6-dien-4-ol (3.22 g, 13.62
mmol) in DCM (50 mL) at -78.degree. C. was treated with ozone until
the observation of a persistent blue colour. Oxygen was bubbled
through until the blue colour was discharged then the mixture
blanketed under nitrogen and treated with a solution of
triphenylphosphine (7.86 g, 30.0 mmol) in DCM (10 mL). The mixture
was allowed to warm slowly to room temperature and solvents
evaporated. The residue was taken into ether (50 mL) and stirred
for 30 min. The precipitate was removed by filtration and the
solvents evaporated. The residue was taken into DCE (100 mL) and
the resulting stirred solution treated with benzylamine (3.27 mL,
30.0 mmol). After 5 min, sodium triacetoxyborohydride (12.70 g,
59.9 mmol) was added portionwise. After 16 h, the mixture was
diluted with DCM (50 mL) washed with aqueous sodium bicarbonate
(250 mL) and concentrated. The residue was stirred in Et.sub.2O (50
mL) for 30 min and the precipitate removed by filtration. The
solvents were evaporated and the residue purified by strong cation
exchange capture-and-release ion exchange chromatography. The
residue was further purified by column chromatography
(DCM/MeOH/NH.sub.3) to afford 2.95 g (69%) of
1-benzyl-4-((1s,4r)-4-propylcyclohexyl)piperidin-4-ol as a yellow
oil. LCMS-ESI (m/z) calculated for C.sub.21H.sub.33NO: 315.3; found
316.8 [M+H].sup.+, t.sub.R=1.97 min (Method 6).
1-benzyl-4-((1s,4r)-4-propylcyclohexyl)-1,2,3,6-tetrahydropyridine
##STR00360##
To a stirring solution of
1-benzyl-4-((1s,4r)-4-propylcyclohexyl)piperidin-4-ol (2.94 g, 9.32
mmol) in DCM (150 mL) was added thionyl chloride (2.38 mL, 32.6
mmol). After 3 h, the mixture was treated with ice-water (50 mL)
and basified with NaOH (2 N aqueous, 30 mL). The layers were
separated and the aqueous layer was further extracted with DCM (50
mL). The combined organic extracts were dried over MgSO.sub.4 and
solvents evaporated. The residue was purified by column
chromatography (DCM/MeOH/NH.sub.3) to afford 1.69 g (61%) of
1-benzyl-4-((1s,4r)-4-propylcyclohexyl)-1,2,3,6-tetrahydropyridine
as a yellow oil. LCMS-ESI (m/z) calculated for C.sub.21H.sub.31N:
297.3; found 298.8 [M+H].sup.+, t.sub.R=2.23 min (Method 6).
4-((1s,4r)-4-propylcyclohexyl)piperidine
##STR00361##
Prepared using General Procedure 18: A solution of
1-benzyl-4-((1s,4r)-4-propylcyclohexyl)-1,2,3,6-tetrahydropyridine
(1.69 g, 5.68 mmol) in MeOH (30 mL) and AcOH (15 mL) was
hydrogenated with the H-cube reactor (55 mm 10% Pd/C Cat-cart,
55.degree. C., 1 mL/min, repeated passes) until such time as the
reaction was adjudged complete by LCMS analysis. The solvents were
evaporated and the residue taken up in DCM (15 mL) and washed with
aqueous sodium bicarbonate (50 mL). The solvents were evaporated
and the residue purified by column chromatography
(DCM/MeOH/NH.sub.3) to afford 869 mg (73%) of
4-((1s,4r)-4-propylcyclohexyl)piperidine as a waxy solid. LCMS-ESI
(m/z) calculated for C.sub.14H.sub.27N: 209.2; found 210.3
[M+H].sup.+, t.sub.R=1.70 min (Method 11).
4-((1s,4r)-4-propylcyclohexyl)pyridine
##STR00362##
A stirring solution of
4-((1s,4r)-4-propylcyclohexyl)hepta-1,6-dien-4-ol (17 g, 71.9 mmol)
in DCM (400 mL) was cooled to -78.degree. C. then treated with
ozone until the observation of a persistent blue colour. Oxygen was
bubbled through until the colour was discharged whereupon
triphenylphosphine (41.5 g, 158 mmol) was added. After 1 h, ammonia
(144 mL of a 7 M solution in MeOH, 1007 mmol) was added. The
mixture was allowed to warm slowly to ambient temperature. After a
further 12 h, solvents were evaporated and the mixture treated with
ether (50 mL). The solid was removed by filtration and the liquors
evaporated. Column chromatography (EA/iso-hexanes) gave 5 g (34%)
of 4-((1s,4r)-4-propylcyclohexyl)pyridine as a yellow oil. LCMS-ESI
(m/z) calculated for C.sub.14H.sub.21N: 203.2; found 204.3
[M+H].sup.+, t.sub.R=1.62 min (Method 11).
4-((1s,4r)-4-propylcyclohexyl)piperidine
##STR00363##
To a stirred solution of 4-(4-propylcyclohexyl)pyridine (10 g, 49.2
mmol) in EtOH/AcOH (2:1, 500 mL) was added 5% rhodium on carbon
(3.04 g, 29.5 mmol). The solution was heated to 75.degree. C. under
a hydrogen atmosphere (5 bar). After 16 h, the mixture was allowed
to cool and filtered through Celite. The solvents were evaporated
and the residue dissolved in EA (60 mL) then washed with NaOH (40
mL of a 2 M aqueous solution). The aqueous layer was further
extracted with EA (2.times.30 ml). The combined organic layers were
dried over MgSO.sub.4 and evaporated to give 9.8 g (95%) of
4-((1s,4r)-4-propylcyclohexyl)piperidine as a white solid. LCMS-ESI
(m/z) calculated for C.sub.14H.sub.27N: 209.2; found 210.3
[M+H].sup.+, t.sub.R=1.70 min (Method 11).
1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1s,4r)-4-pro-
pylcyclohexyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-c-
arboxylic acid (Compound 1413)
##STR00364##
Prepared using General Procedure 11: To a stirring solution of
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) (341 mg,
0.597 mmol) and 4-((1s,4r)-4-propylcyclohexyl)piperidine (150 mg,
0.716 mmol) in toluene (9 mL, degassed) were added sodium
tert-butoxide (230 mg, 2.39 mmol), BINAP (37.2 mg, 0.060 mmol) and
Pd.sub.2(dba).sub.3 (54.7 mg, 0.060 mmol). The resulting reaction
mixture was degassed again at 40.degree. C., before being heated at
100.degree. C. After 16 h, the mixture was allowed to cool then
poured onto 1 M HCl (10 mL) and extracted with EA (3.times.20 mL).
The combined organic extracts were dried over MgSO.sub.4 and
solvents evaporated. Column chromatography
(EA/AcOH/DCM/iso-hexanes) followed by re-slurry from ACN gave 84 mg
(20%) of
1-((S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1
s,4r)-4-propylcyclohexyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoyl)a-
zetidine-3-carboxylic acid (Compound 1413). LCMS-ESI (m/z)
calculated for C.sub.40H.sub.53N.sub.5O.sub.4S: 699.4; found 700.3
[M+H].sup.+, t.sub.R=3.29 min (Method 11). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.78 (s, 1H), 8.72 (app dd, J=8.3, 3.9 Hz,
1H), 8.54 (app d, J=2.0 Hz, 2H), 8.28-7.99 (m, 2H), 7.69 (app dd,
J=3.9, 1.3 Hz, 1H), 7.37 (app d, J=8.1 Hz, 2H), 6.92 (app dd,
J=3.9, 1.8 Hz, 1H), 4.63 (p, J=7.8, 6.8 Hz, 1H), 4.45-4.41 (m,
0.5H), 4.31-4.27 (m, 0.5H), 4.16 (q, J=7.0, 5.4 Hz, 1H), 4.03 (dt,
J=19.2, 9.4 Hz, 1H), 3.90 (app t, J=8.4 Hz, 3H), 3.47-3.40 (m,
0.5H), 3.31-3.27 (m, 0.5H), 3.18-2.85 (m, 2H), 2.71 (t, J=11.6 Hz,
2H), 1.74 (d, J=10.9 Hz, 6H), 1.37-1.20 (m, 15H), 1.20-0.90 (m,
5H), 0.85 (t, J=7.3 Hz, 5H).
Compound 1414 was prepared from
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(4-(tert-butyl)benzamido)propan-
oic acid (INT-27) using General Procedures 7, 4 and 11
sequentially.
Compounds 1415 and 1416 was prepared from (S)-tert-butyl
3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxam-
ido)propanoate (INT-17) using General Procedures 8, 7, 4 and 11
sequentially.
Compounds 1417 and 1418 were prepared from tert-butyl
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylate (INT-38) using General
Procedures 10 then 8.
Compound 1419 were prepared from (S)-tert-butyl
1-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)pyrrolidine-2-carboxylate (INT-54) using
General Procedures 8 and 11 sequentially.
Compounds 1421-1423 were prepared from
(rac)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-
-carboxamido)propanoyl)azetidine-3-carboxylic acid (racemic-INT-71)
using General Procedure 11.
Appropriately substituted 4-(4-alkylcyclohexyl)piperidines were
prepared from the corresponding 4-alkylcyclohexanones and
4-bromopyridine using General Procedures 37 and 18
sequentially.
Compounds 1424, 1427-1429, 1431, 1438, and 1439 were prepared from
the appropriately substituted 4-(4-alkylcyclohexyl)piperidines and
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)-azetidine-3-carboxylic acid (INT-71) using
General Procedure 11.
Compounds 1425, 1426 and 1430 were prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) using
General Procedure 11.
4-(4-propylphenyl)piperazine was prepared from
4-propylphenylmagnesium bromide and 1-benzylpiperidin-4-one using
the conditions of General Procedures 38, 39 and 18
sequentially.
Compound 1432 was prepared from 4-(4-propylphenyl)piperazine and
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) using
General Procedure 11.
Compound 1433 was prepared from (S)-tert-butyl
3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carboxam-
ido)propanoate (INT-17) using General Procedures 8, 7, 8 and 11
sequentially.
1-(4-propylcyclohexyl)piperidin-4-one was prepared from
4-propylcyclohexanone and piperidin-4-ol using General Procedures
15 and 24 sequentially.
Compound 1434 was prepared from
1-(4-propylcyclohexyl)piperidin-4-one and
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) using
General Procedure 37.
1-(4-propylcyclohexyl)piperazine was prepared from
4-propylcyclohexanone and benzyl piperazine-1-carboxylate using
General Procedures 15 and 18 sequentially.
Compounds 1435 and 1436 were prepared from
1-(4-propylcyclohexyl)piperazine and
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) using
General Procedure 11.
Compound 1437 was prepared from
(R)-2-((S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-
-2-carboxamido)propanamido)propanoic acid (INT-72) using General
Procedure 11.
2-methoxy-5-(4-((1s,4r)-4-propylcyclohexyl)piperidin-1-yl)pyrimidine
##STR00365##
Prepared using General Procedure 11: A stirring solution of sodium
tert-butoxide (2.203 g, 22.93 mmol),
4-((1s,4r)-4-propylcyclohexyl)piperidine (1.600 g, 7.64 mmol) and
5-bromo-2-methoxypyrimidine (1.444 g, 7.64 mmol) in toluene (60 mL)
was purged with nitrogen for 10 mins.
2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (0.095 g, 0.153
mmol) and Pd.sub.2dba.sub.3 (0.064 g, 0.076 mmol) were added and
purging was continued for a further 10 minutes. The reaction
mixture was then heated to 100.degree. C. and stirred under
nitrogen for 1.5 h. The reaction was allowed to cool then diluted
with water (100 mL) and extracted with EA (2.times.100 mL). The
combined organic layers were dried over MgSO.sub.4 and solvents
evaporated. The residue was purified through a silica plug (DCM/EA)
to afford 2.04 g (84%) of
2-methoxy-5-(4-((1s,4r)-4-propylcyclohexyl)piperidin-1-yl)pyrimidine.
LCMS-ESI (m/z) calculated for C.sub.19H.sub.31N.sub.3O: 317.3;
found 318.3 [M+H].sup.+, t.sub.R=2.27 min (Method 11).
5-(4-((1s,4r)-4-propylcyclohexyl)piperidin-1-yl)pyrimidin-2-ol
##STR00366##
To a stirring mixture of HCl (50 mL of a 6 M solution in IPA) and
THF (60 mL) was added
2-methoxy-5-(4-((1s,4r)-4-propylcyclohexyl)piperidin-1-yl)pyrimidine
(2 g, 6.30 mmol) and the mixture heated under reflux. After 7 h,
solvents were evaporated and the residue triturated with Et.sub.2O
(25 mL) to afford 1.8 g (94%) of
5-(4-((1s,4r)-4-propylcyclohexyl)piperidin-1-yl)pyrimidin-2-ol as a
yellow solid. LCMS-ESI (m/z) calculated for
C.sub.18H.sub.29N.sub.3O: 303.2; found 304.3 [M+H].sup.+,
t.sub.R=1.65 min (Method 11).
2-chloro-5-(4-((1s,4r)-4-propylcyclohexyl)piperidin-1-yl)pyrimidine
(INT-80)
##STR00367##
A stirring solution of
5-(4-((1s,4r)-4-propylcyclohexyl)piperidin-1-yl)pyrimidin-2-ol (1.8
g, 5.93 mmol) in phosphoryl trichloride (10 mL, 109 mmol) was
heated to 100.degree. C. After 2 h, the mixture was evaporated and
the residue dissolved in DCM (20 mL) and washed with NaHCO.sub.3
(20 mL). The organic layer was dried over MgSO.sub.4 and
evaporated. The residue was triturated from acetonitrile (20 mL) to
afford 1.12 g (59%) of
2-chloro-5-(4-((1s,4r)-4-propylcyclohexyl)piperidin-1-yl)pyrimidine
(INT-80) as a beige solid. LCMS-ESI (m/z) calculated for
C.sub.18H.sub.28Cl N.sub.3: 321.2; found 322.5 [M+H].sup.+,
t.sub.R=2.30 min (Method 11).
(S)-tert-butyl(3-(4-bromophenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)ca-
rbamate
##STR00368##
Prepared using General Procedure 7. To a stirring solution of
(S)-3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid
(1 g, 2.91 mmol) in DCM (20 mL) was added methanesulfonamide (2.76
g, 29.1 mmol), DIEA (2.53 ml, 14.53 mmol) and DMAP (0.710 g, 5.81
mmol) followed by EDC (0.780 g, 4.07 mmol). After 100 h, the
mixture was filtered, diluted with DCM (30 mL) and washed with
saturated aqueous NH.sub.4Cl (50 mL). The organics were dried over
MgSO.sub.4 and solvents evaporated to afford 1.154 g (94%) of
(S)-tert-butyl (3-(4-bromophenyl)-1-(methyl
sulfonamido)-1-oxopropan-2-yl)carbamate. LCMS-ESI (m/z) calculated
for C.sub.15H.sub.21BrN.sub.2O.sub.5S: 420.0; found 443.1
[M+Na].sup.+, t.sub.R=2.19 min (Method 11).
(S)-2-amino-3-(4-bromophenyl)-N-(methylsulfonyl)propanamide
hydrochloride
##STR00369##
Prepared using General Procedure 8. To a stirring solution of
(S)-tert-butyl
(3-(4-bromophenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)carbamate
(1.15 g, 2.73 mmol) in DCM (20 mL) was added HCl (0.83 mL of a 4 M
solution in dioxane, 3.32 mmol). After 16 h, the precipitate was
collected by filtration to afford 0.673 g (69%) of
(S)-2-amino-3-(4-bromophenyl)-N-(methyl sulfonyl)propanamide
hydrochloride as a white solid. LCMS-ESI (m/z) calculated for
C.sub.10H.sub.13BrN.sub.2O.sub.3S: 320.0; found 321.0 [M+H].sup.+,
t.sub.R=1.08 min (Method 11).
(S)--N-(3-(4-bromophenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)-5-(tert--
butyl)thiophene-2-carboxamide
##STR00370##
Prepared using General Procedure 7. To a stirring solution of
5-(tert-butyl)thiophene-2-carboxylic acid (0.229 g, 1.241 mmol) and
DIEA (0.72 ml, 4.14 mmol) in DMF (5 mL) was added HATU (0.472 g,
1.241 mmol) followed by
(S)-2-amino-3-(4-bromophenyl)-N-(methylsulfonyl)propanamide
hydrochloride (0.37 g, 1.035 mmol). After 2 h, the mixture was
diluted with water (20 mL) and extracted with EA (2.times.30 mL).
The combined organic layers were washed with brine (3.times.100 mL)
dried over MgSO.sub.4 and solvents evaporated. Column
chromatography (Et.sub.2O/AcOH/DCM/iso-hexanes) gave 282 mg (56%)
of
(S)--N-(3-(4-bromophenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)-5-(tert-
-butyl)thiophene-2-carboxamide as white solid. LCMS-ESI (m/z)
calculated for C.sub.19H.sub.23BrN.sub.2O.sub.4S.sub.2: 486.0;
found 487.0 [M+H].sup.+, t.sub.R=2.53 min (Method 11).
(S)-5-(tert-butyl)-N-(1-(methylsulfonamido)-1-oxo-3-(4-(4,4,5,5-tetramethy-
l-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)thiophene-2-carboxamide
(INT-81)
##STR00371##
To a stirring solution of
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.169
g, 0.667 mmol) and
(S)--N-(3-(4-bromophenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)-5-(tert-
-butyl)thiophene-2-carboxamide (0.271 g, 0.556 mmol) in dioxane (4
mL) was added potassium acetate (0.164 g, 1.668 mmol) and the
mixture de-gassed. PdCl.sub.2dppf (0.020 g, 0.028 mmol) was added
and the mixture then heated under reflux for 2 h. The mixture was
allowed to cool then diluted with 1 M HCl (10 mL) and extracted
with EA (2.times.20 mL). The combined organic layers were dried
over MgSO.sub.4 and solvents evaporated. Column chromatography
(EA/AcOH/DCM/iso-hexanes) gave 0.22 g (74%) of
(S)-5-(tert-butyl)-N-(1-(methylsulfonamido)-1-oxo-3-(4-(4,4,5,5-tetrameth-
yl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)thiophene-2-carboxamide
as a white solid (INT-81). LCMS-ESI (m/z) calculated for
C.sub.25H.sub.35BN.sub.2O.sub.6S.sub.2: 534.2; found 535.2
[M+H].sup.+, t.sub.R=7.61 min (Method 10).
5-(tert-butyl)-N--((S)-1-(methylsulfonamido)-1-oxo-3-(4-(5-(4-((1s,4r)-4-p-
ropylcyclohexyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propan-2-yl)thiophene-
-2-carboxamide (Compound 1438)
##STR00372##
Prepared using General Procedure 10. To a stirring solution of
2-chloro-5-(4-((1s,4r)-4-propylcyclohexyl)piperidin-1-yl)pyrimidine
(INT-80) (0.143 g, 0.445 mmol) and (S)-5-(tert-butyl)-N-(1-(methyl
sulfonamido)-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phen-
yl)propan-2-yl)thiophene-2-carboxamide (INT-81) (0.216 g, 0.404
mmol) in dioxane (1.5 mL) and toluene (1.5 mL) was added a solution
of NaHCO.sub.3 (0.102 g, 1.212 mmol) in water (1 mL) and the
mixture de-gassed. PdCl.sub.2dppf (0.030 g, 0.040 mmol) was added
and the mixture heated under reflux. After 6 h, the mixture was
allowed to cool then poured into 1 M HCl (20 mL) and extracted with
EA (2.times.50 mL). The combined organic layers were dried over
MgSO.sub.4 and solvents evaporated. Column chromatography
(EA/AcOH/DCM/iso-hexanes) gave 0.17 g (61%) of
5-(tert-butyl)-N--((S)-1-(methylsulfonamido)-1-oxo-3-(4-(5-(4-((1s,4r)-4--
propylcyclohexyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propan-2-yl)thiophen-
e-2-carboxamide (Compound 1438). LCMS-ESI (m/z) calculated for
C.sub.37H.sub.51N.sub.5O.sub.4S.sub.2: 693.3; found 694.4
[M+H].sup.+, t.sub.R=11.63 min (Method 10). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.18 (s, 1H), 8.69 (d, J=7.8 Hz, 1H), 8.54
(s, 2H), 8.26-8.01 (m, 2H), 7.67 (d, J=3.9 Hz, 1H), 7.45 (d, J=8.2
Hz, 2H), 6.93 (d, J=3.8 Hz, 1H), 4.73-4.67 (m, 1H), 3.91 (d, J=12.4
Hz, 2H), 3.23 (s, 3H), 3.22-3.13 (m, 1H), 3.03 (dd, J=13.7, 10.7
Hz, 1H), 2.71 (t, J=11.6 Hz, 2H), 1.74 (app d, J=10.7 Hz, 6H),
1.33-1.21 (m, 14H), 1.18-1.09 (m, 3H), 1.05-0.75 (m, 8H).
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carbo-
xamido)propanoic acid
##STR00373##
Prepared using General Procedure 8: To a stirring solution of
tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoate (INT-17) (12.0 g, 21.60 mmol) in DCM (180 mL)
was added TFA (120 mL). After 3 h, the solution was poured into
ice-water (300 ml) and separated. The organic layer was washed with
water (2.times.300 mL), dried over MgSO.sub.4, and solvents
evaporated to afford 10.55 g (100%) of
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoic acid. LCMS-ESI (m/z) calculated for
C.sub.22H.sub.22BrN.sub.3O.sub.3S: 487.1; found 488.1 [M+H].sup.+,
t.sub.R=2.60 min (Method 11).
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1s,4r)-4-propyl-
cyclohexyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoic acid
(Compound 1439)
##STR00374##
Prepared using General Procedure 11. A 250-ml round-bottomed flask
equipped for magnetic stirring was charged with cesium carbonate
(12.01 g, 36.9 mmol) and heated to 150.degree. C. under vacuum.
After 5 h, the flask was allowed to cool to 85.degree. C.,
blanketed under N.sub.2, then treated with dioxane (100 mL) and
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoic acid (4 g, 8.19 mmol) and
4-((1s,4r)-4-propylcyclohexyl)piperidine (2.058 g, 9.83 mmol). The
mixture was de-gassed then treated with Xantphos Pd G3 (0.311 g,
0.328 mmol). After 16 h, the mixture was again de-gassed then
treated with further 4-((1s,4r)-4-propylcyclohexyl)piperidine
(0.909 g, 4.34 mmol) and further Xantphos Pd G3 (0.311 g, 0.328
mmol). After a further 4 h, the mixture was treated with further
Xantphos Pd G3 (0.311 g, 0.328 mmol). After a further 20 h, the
mixture was allowed to cool then treated with DMSO (30 mL) and AcOH
(2.3 ml, 41.0 mmol). After 1 h, the mixture was poured into a
mixture of water (100 mL), THF (50 mL), AcOH (10 mL) and DCM (100
mL). After stirring for 1 h, the layers were separated and the
aqueous diluted with water (100 mL) and AcOH (2 mL) then extracted
with DCM (100 mL). The combined organic extracts were washed with a
mixture of water (100 mL) and AcOH (2 mL) and evaporated. Column
chromatography (AcOH/THF/DCM) gave moderately pure product that was
then re-slurried from ACN (25 mL) to afford 1.66 g (31%) of
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1s,4r)-4-propy-
lcyclohexyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoic acid
(Compound 1439) as a yellow solid. LCMS-ESI (m/z) calculated for
C.sub.36H.sub.48N.sub.4O.sub.3S: 616.3; found 617.4 [M+H].sup.+,
t.sub.R=2.60 min (Method 10).
Compound 1440 was prepared from tert-butyl
(S)-3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-carb-
oxamido)propanoate (INT-17) using General Procedures 8 and 11
sequentially.
Compounds 1441 and 1442 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1s,4r)-4-propy-
lcyclohexyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoic acid
(Compound 1439) using General Procedure 7.
Compounds 1443-1460 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1s,4r)-4-propy-
lcyclohexyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoic acid
(Compound 1439) using General Procedures 7 then 4.
Compounds 1461-1470 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1s,4r)-4-propy-
lcyclohexyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoic acid
(Compound 1439) using General Procedures 7 then 8.
Compounds 1471-1473 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1s,4r)-4-propy-
lcyclohexyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoic acid
(Compound 1439) using General Procedures 7, 4, then 8.
Compounds 1474-1493 were prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) using
General Procedure 11.
1-bromo-4-propoxybenzene
##STR00375##
Prepared using General Procedure 12. To a stirring mixture of
mixture of 4-bromophenol (2 g, 11.56 mmol) and potassium carbonate
(1.743 g, 12.61 mmol) in DMF (20 mL) was added 1-iodopropane (1.537
mL, 15.76 mmol) and the mixture heated to 90.degree. C. After 16 h,
the mixture was poured onto water (100 mL) and extracted with
Et.sub.2O (2.times.100 mL). The combined organics were dried over
MgSO.sub.4 and solvents evaporated. Column chromatography
(Et.sub.2O/iso-hexanes) gave 2.2 g (97%) of
1-bromo-4-propoxybenzene as a colourless oil. LCMS-ESI (m/z)
calculated for C.sub.9H.sub.11BrNO: 214.0; not recorded. .sup.1H
NMR (400 MHz, Chloroform-d) .delta. 7.42-7.34 (m, 2H), 6.86-6.73
(m, 2H), 3.91 (t, J=6.6 Hz, 2H), 1.82 (app dtd, J=13.9, 7.4, 6.5
Hz, 2H), 1.05 (t, J=7.4 Hz, 3H).
1-benzyl-4-(4-propoxyphenyl)piperidin-4-ol
##STR00376##
Prepared using General Procedure 38. To a stirring solution of
1-bromo-4-propoxybenzene (2.2 g, 10.23 mmol) in THF (25 mL) at
-78.degree. C. was added dropwise butyllithium (4.46 mL of a 2.5 M
solution in hexanes 11.16 mmol). After 1 h, 1-benzylpiperidin-4-one
(1.72 mL, 9.30 mmol) was added. The reaction mixture was allowed to
warm slowly and stirred at ambient temperature. After 16 h, the
mixture was quenched with NH.sub.4Cl (30 mL) and extracted with EA
(3.times.30 mL). The combined organic layers were washed with brine
(30 mL), dried over MgSO.sub.4 and solvents evaporated to give 3.03
g (100%) of 1-benzyl-4-(4-propoxyphenyl)piperidin-4-ol as a yellow
oil. LCMS-ESI (m/z) calculated for C.sub.21H.sub.27NO.sub.2: 325.2;
found 326.2 [M+H].sup.+, t.sub.R=1.41 min (Method 11).
1-benzyl-4-(4-propoxyphenyl)-1,2,3,6-tetrahydropyridine
##STR00377##
Prepared using General Procedure 39. To a stirring solution of
1-benzyl-4-(4-propoxyphenyl)piperidin-4-ol (3.02 g, 9.28 mmol) in
DCM (15 mL) was added TFA (15 mL). After 2.5 h, the solvents were
evaporated and the residue diluted with saturated aqueous
NaHCO.sub.3 (35 mL) and extracted with DCM (2.times.30 mL). The
combined organic extracts were dried over MgSO.sub.4 and solvents
evaporated. Column chromatography (EA/iso-hexanes) gave 896 mg
(31%) of 1-benzyl-4-(4-propoxyphenyl)-1,2,3,6-tetrahydropyridine as
a yellow oil. LCMS-ESI (m/z) calculated for C.sub.14H.sub.21NO:
219.2; found 220.2 [M+H].sup.+, t.sub.R=1.23 min (Method 11).
4-(4-propoxyphenyl)piperidine
##STR00378##
Prepared using General Procedure 18: To a stirring solution of
1-benzyl-4-(4-propoxyphenyl)-1,2,3,6-tetrahydropyridine (896 mg,
2.91 mmol) in MeOH (15 mL) was added ammonium formate (551 mg, 8.74
mmol). After complete dissolution, Pd/C (286 mg of Johnson and
Matthey Type 39 paste) was added and the reaction mixture heated
under reflux for 4 h. The mixture was allowed to cool and filtered
through a glass microfiber filter, washing with MeOH. The solvents
were evaporated and the residue purified by column chromatography
(NH.sub.3/MeOH/DCM) to afford 350 mg (55%) of
4-(4-propoxyphenyl)piperidine as an off-white solid. LCMS-ESI (m/z)
calculated for C.sub.14H.sub.21NO: 219.2; found 220.2 [M+H].sup.+,
t.sub.R=0.84 min (Method 11).
Compound 1494 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
4-(4-propoxyphenyl)piperidine using General Procedure 11.
1-bromo-4-(2-methoxyethyl)benzene
##STR00379##
To a stirring mixture of 2-(4-bromophenyl)ethanol (2 g, 9.95 mmol)
in DMF (20 ml) at 0.degree. C. was added sodium hydride (0.438 g of
a 60% dispersion in mineral oil, 10.94 mmol). After 45 min, the
cooling bath was removed and iodomethane (0.743 mL, 11.94 mmol) was
added to the reaction mixture. After 3 h, the mixture was poured
onto water (150 mL) and extracted with EA (3.times.50 mL). The
combined organic extracts were dried over MgSO.sub.4 and solvents
evaporated. Column chromatography (Et.sub.2O/iso-hexanes) gave 1.9
g (89%) of 1-bromo-4-(2-methoxyethyl)benzene) as an orange oil.
LCMS-ESI (m/z) calculated for C.sub.9H.sub.11BrNO: 214.0; not
recorded. .sup.1H NMR (400 MHz, Chloroform-d) .delta. 7.50-7.38 (m,
2H), 7.15-7.07 (m, 2H), 3.60 (t, J=6.8 Hz, 2H), 3.37 (s, 3H), 2.85
(t, J=6.9 Hz, 2H).
4-(4-(2-methoxyethyl)phenyl)piperidine
##STR00380##
Following the sequence as described for the preparation of
4-(4-propoxyphenyl)piperidine from 1-bromo-4-propoxybenzene,
1-bromo-4-(2-methoxyethyl)benzene gave
4-(4-(2-methoxyethyl)phenyl)piperidine as a white solid. LCMS-ESI
(m/z) calculated for C.sub.14H.sub.21NO: 219.2; found 220.2
[M+H].sup.+, t.sub.R=0.84 min (Method 11).
Compound 1495 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
4-(4-(2-methoxyethyl)phenyl)piperidine using General Procedure
11.
4-((1s,4r)-4-propylcyclohexyl)piperidin-2-one
##STR00381##
To a stirring solution of N-chlorosuccinimide (217 mg, 1.629 mmol)
in Et.sub.2O (3 mL) at 0.degree. C. was added a solution of
4-((1s,4r)-4-propylcyclohexyl)piperidine (310 mg, 1.481 mmol) in
Et.sub.2O (3 mL) dropwise. After 16 h, the mixture was filtered,
washing with Et.sub.2O (20 mL). The filtrate was washed
successively with water (20 mL) and brine (20 mL) dried over
Na.sub.2SO.sub.4, filtered, and partially evaporated (to .about.4
mL). This solution was then added dropwise to a stirring mixture of
potassium hydroxide (205 mg, 3.10 mmol) and EtOH (6 mL). After 16
h, the mixture was filtered and washed with EtOH (6 mL). The
solvents were partially evaporated (to .about.3 mL) and the residue
diluted with water (20 mL) and extracted with Et.sub.2O (2.times.30
mL). The combined organic extracts were washed with brine (20 mL),
dried over Na.sub.2SO.sub.4 and solvents partially evaporated (to
.about.4 mL). This solution was then added to a stirring suspension
of NaClO.sub.2 (680 mg, 7.52 mmol), NaH.sub.2PO.sub.4 (868 mg, 7.23
mmol) and 2-methylbut-2-ene (7.2 mL of a 2 M solution in THF, 14.4
mmol) in THF (12 mL) and water (6 mL) at 0.degree. C. After 16 h,
the reaction mixture was diluted with EA (50 ml) and washed
successively with saturated aqueous Na.sub.2S.sub.2O.sub.3
(2.times.30 mL) and brine (30 mL). The organic layer was dried over
MgSO.sub.4 and solvents evaporated. Column chromatography
(DCM/MeOH) gave 82 mg (25%) of
4-((1s,4r)-4-propylcyclohexyl)piperidin-2-one as a white solid.
LCMS-ESI (m/z) calculated for C.sub.14H.sub.25NO: 223.2; found
224.2 [M+H].sup.+, t.sub.R=2.43 min (Method 11).
Compound 1496 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
4-((1s,4r)-4-propylcyclohexyl)piperidin-2-one using General
Procedure 11.
3-amino-2,2-dimethyl-1-(4-propylpiperidin-1-yl)propan-1-one
##STR00382##
Prepared using General Procedures 7 and 8 sequentially. To a
stirring solution of DIEA (1.7 mL, 9.21 mmol), 4-propylpiperidine
(0.615 g, 4.83 mmol) and
3-((tert-butoxycarbonyl)amino)-2,2-dimethylpropanoic acid (1 g,
4.60 mmol) in DMF (10 mL) was added HATU (1.925 g, 5.06 mmol).
After 1 h, the mixture was poured into water (100 mL) and extracted
with EA (3.times.30 mL). The combined organic extracts were washed
successively with 1 M HCl (2.times.50 mL), saturated aqueous
NaHCO.sub.3 (2.times.50 mL) and brine (20 mL), dried over
MgSO.sub.4 and evaporated. Column chromatography
(acetone/iso-hexanes) gave the protected intermediate that was
dissolved in DCM (8 mL) and treated with TFA (2 mL). After 3 h, the
mixture was diluted with toluene (10 mL) and solvents evaporated.
The residue was dissolved in DCM (20 mL), washed with saturated
aqueous NaHCO.sub.3 (50 mL), dried over Na.sub.2SO.sub.4 and
solvents evaporated to afford 665 mg (64%) of
3-amino-2,2-dimethyl-1-(4-propylpiperidin-1-yl)propan-1-one.
LCMS-ESI (m/z) calculated for C.sub.13H.sub.26N.sub.2O: 226.2;
found 227.2 [M+H].sup.+, t.sub.R=1.31 min (Method 11).
Compound 1497 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
3-amino-3-methyl-1-(4-propylpiperidin-1-yl)butan-1-one using
General Procedure 11.
(E)-5-bromo-2-(prop-1-en-1-yl)pyridine
##STR00383##
Prepared using General Procedure 10. To a stirring solution of
5-bromo-2-iodopyridine (1.226 g, 4.32 mmol) and
(E)-4,4,5,5-tetramethyl-2-(prop-1-en-1-yl)-1,3,2-dioxaborolane
(0.871 g, 5.18 mmol) in dioxane (20 mL) was added NaHCO.sub.3 (12
mL of a 0.9 M aqueous solution, 10.80 mmol) and the mixture
de-gassed. PdCl.sub.2dppf (0.158 g, 0.216 mmol) was charged and the
mixture heated under reflux. After 1 h, the mixture was allowed to
cool then poured into saturated aqueous NH.sub.4Cl (20 mL) and
extracted with EA (2.times.60 ml). The combined organics were dried
over MgSO.sub.4 and solvents evaporated. Column chromatography
(EA/iso-hexanes) gave 605 mg (71%) of
(E)-5-bromo-2-(prop-1-en-1-yl)pyridine (605 mg, 2.57 mmol, 59.4%
yield) as a white solid. LCMS-ESI (m/z) calculated for
C.sub.8H.sub.8BrN: 197.0; found 198.0 [M+H].sup.+, t.sub.R=2.03 min
(Method 11).
(E)-tert-butyl
6-(prop-1-en-1-yl)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate
##STR00384##
Prepared using General Procedure 10. To a stirring solution of
(E)-5-bromo-2-(prop-1-en-1-yl)pyridine (605 mg, 3.05 mmol) and
tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (1228 mg, 3.97 mmol) in dioxane (16 mL) was added
saturated aqueous NaHCO.sub.3 (8.5 mL, .about.7.64 mmol) and the
mixture de-gassed. PdCl.sub.2dppf (112 mg, 0.153 mmol) was added
and the mixture heated under reflux. After 1 h, the mixture was
allowed to cool then treated with water (10 mL) and extracted with
EA (3.times.20 mL), dried over MgSO.sub.4 and solvents evaporated.
Column chromatography (EA/iso-hexanes) gave 565 mg (62%) of
(E)-tert-butyl
6-(prop-1-en-1-yl)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate
as an orange oil. LCMS-ESI (m/z) calculated for
C.sub.18H.sub.24N.sub.2O.sub.2: 300.2; found 301.2 [M+H].sup.+,
t.sub.R=1.66 min (Method 11).
tert-butyl 4-(6-propylpyridin-3-yl)piperidine-1-carboxylate
##STR00385##
Prepared using General Procedure 18. A solution of (E)-tert-butyl
6-(prop-1-en-1-yl)-5',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate
(565 mg, 1.881 mmol) in MeOH (60 mL) was hydrogenated in the H-Cube
(10% Pd/C, 30.times.4 mm Cat-Cart, full hydrogen, 50.degree. C.,
1.5 mL/min). Solvents were evaporated to afford 478 mg (83%) of
tert-butyl 4-(6-propylpyridin-3-yl)piperidine-1-carboxylate as a
pale yellow oil. LCMS-ESI (m/z) calculated for
C.sub.18H.sub.28N.sub.2O.sub.2: 304.2; found 305.2 [M+H].sup.+,
t.sub.R=1.44 min (Method 11).
5-(piperidin-4-yl)-2-propylpyridine hydrochloride
##STR00386##
Prepared using General Procedure 8. To a stirring solution of
tert-butyl 4-(6-propylpyridin-3-yl)piperidine-1-carboxylate (478
mg, 1.570 mmol) in dioxane (8 ml) was added HCl (3.93 ml of a 4 M
solution in dioxane, 15.70 mmol). After 16 h, solvents were
evaporated to afford 378 mg (100%) of
5-(piperidin-4-yl)-2-propylpyridine hydrochloride. LCMS-ESI (m/z)
calculated for C.sub.13H.sub.20N.sub.2: 204.2; found 205.2
[M+H].sup.+, t.sub.R=0.15 min (Method 11).
Compound 1498 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
5-(piperidin-4-yl)-2-propylpyridine hydrochloride using General
Procedure 11.
2-(piperidin-4-yl)-5-propylpyrimidine hydrochloride
##STR00387##
Following an analogous sequence to that described for the
preparation of 5-(piperidin-4-yl)-2-propylpyridine hydrochloride,
5-bromo-2-iodopyrimidine gave 2-(piperidin-4-yl)-5-propylpyrimidine
hydrochloride. LCMS-ESI (m/z) calculated for
C.sub.12H.sub.19N.sub.3: 205.2; found 206.2 [M+H].sup.+,
t.sub.R=0.71 min (Method 11).
Compound 1499 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
2-(piperidin-4-yl)-5-propylpyrimidine hydrochloride using General
Procedure 11.
tert-butyl
4-(4-(cyanomethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate
##STR00388##
Prepared using General Procedure 10: A stirring solution of
tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (1.703 g, 5.51 mmol) and 2-(4-bromophenyl)acetonitrile
(1.2 g, 6.12 mmol) in dioxane (8 mL) was treated with a solution of
NaHCO.sub.3 (1.286 g, 15.30 mmol) in water (4 mL) and de-gassed.
PdCl.sub.2dppf (0.224 g, 0.306 mmol) was charged and the mixture
heated under reflux. After 5 h, the mixture was allowed to cool
then poured into water (100 mL) and extracted with EA (2.times.100
mL). The combined organics were dried over MgSO.sub.4 and solvents
evaporated. Column chromatography (EA/iso-hexane/DCM) gave 1.388 g
(76%) of tert-butyl
4-(4-(cyanomethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as
a pale yellow solid. LCMS-ESI (m/z) calculated for
C.sub.18H.sub.22N.sub.2O.sub.2: 298.2; found 321.1 [M+Na].sup.+,
t.sub.R=2.45 min (Method 11).
tert-butyl 4-(4-(cyanomethyl)phenyl)piperidine-1-carboxylate
##STR00389##
Prepared using General Procedure 18. To a stirring solution of
tert-butyl
4-(4-(cyanomethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate
(1.09 g, 3.65 mmol) in a mixture of EtOH (30 mL) and THF (10 mL)
was added 180 mg of Pd/C (180 mg of Johnson and Matthey Type 38H
Paste) and the mixture hydrogenated under 2 bar. After 1 h, the
mixture was filtered and solvents evaporated to afford 1.09 g
(100%) of tert-butyl
4-(4-(cyanomethyl)phenyl)piperidine-1-carboxylate as a grey solid.
LCMS-ESI (m/z) calculated for C.sub.18H.sub.24N.sub.2O.sub.2:
300.2; found 301.2 [M+H].sup.+, t.sub.R=2.48 min (Method 11).
2-(4-(piperidin-4-yl)phenyl)acetonitrile hydrochloride
##STR00390##
Prepared using General Procedure 8: To a stirring solution of
tert-butyl 4-(4-(cyanomethyl)phenyl)piperidine-1-carboxylate (1.09
g, 3.63 mmol) in dioxane (10 mL) was added HCl (5 mL of a 4 M
solution in dioxane, 20 mmol). After 16 h, solvents were evaporated
to give 859 mg (100%) of 2-(4-(piperidin-4-yl)phenyl)acetonitrile
hydrochloride as a light brown solid. LCMS-ESI (m/z) calculated for
C.sub.13H.sub.16N.sub.2: 200.2; found 201.1 [M+H].sup.+,
t.sub.R=0.44 min (Method 11).
Compound 1500 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
2-(4-(piperidin-4-yl)phenyl)acetonitrile hydrochloride using
General Procedure 11.
3-(piperidin-4-yl)-6-propylpyridazine hydrochloride
##STR00391##
Following an analogous sequence to that described for the
preparation of 5-(piperidin-4-yl)-2-propylpyridine hydrochloride,
3,6-dibromopyridazine gave 3-(piperidin-4-yl)-6-propylpyridazine
hydrochloride. LCMS-ESI (m/z) calculated for
C.sub.12H.sub.19N.sub.3: 205.2; found 206.2 [M+H].sup.+,
t.sub.R=0.23 min (Method 11).
Compound 1501 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
3-(piperidin-4-yl)-6-propylpyridazine hydrochloride using General
Procedure 11.
tert-butyl
3-(2-((4-methoxyphenyl)sulfonyl)hydrazono)azetidine-1-carboxyla-
te
##STR00392##
To a stirring mixture of tert-butyl 3-oxoazetidine-1-carboxylate
(1.693 g, 9.89 mmol) in toluene (30 mL) was added
4-methoxybenzenesulfonohydrazide (2 g, 9.89 mmol) and the mixture
heated under reflux until complete dissolution was observed. After
a further 2 h, the mixture was allowed to cool and solvents
evaporated to afford 3.43 g (98%) of tert-butyl
3-(2-((4-methoxyphenyl)sulfonyl)hydrazono)azetidine-1-carboxylate
as a white solid. LCMS-ESI (m/z) calculated for
C.sub.15H.sub.21N.sub.3O.sub.5S: 355.1; found 299.9
[M+H-tBu].sup.+, t.sub.R=1.64 min (Method 11).
tert-butyl 3-(4-propylphenyl)azetidine-1-carboxylate
##STR00393##
A vial was charged with tert-butyl
3-(2-((4-methoxyphenyl)sulfonyl)hydrazono)azetidine-1-carboxylate
(1 g, 2.81 mmol), (4-propylphenyl)boronic acid (0.69 g, 4.22 mmol)
and Cs.sub.2CO.sub.3 (1.375 g, 4.22 mmol) then dried under vacuum
for 10 min. The tube was backfilled with nitrogen, then treated
with dioxane (10 mL) and de-gassed. The mixture was then heated to
110.degree. C. (sealed vial, bath temperature) with stirring for 18
h. The mixture was allowed to cool then treated with saturated
aqueous NaHCO.sub.3 (10 mL) and DCM (10 mL). The organics were
split off through a hydrophobic frit and evaporated. Column
chromatography (EA/iso-hexanes) gave 109 mg (14%) of tert-butyl
3-(4-propylphenyl)azetidine-1-carboxylate as a colourless oil.
LCMS-ESI (m/z) calculated for C.sub.17H.sub.25NO.sub.2: 275.2;
found 220.1 [M+H-tBu].sup.+, t.sub.R=2.93 min (Method 11).
3-(4-propylphenyl)azetidine
##STR00394##
Prepared using General Procedure 8: To a stirring solution of
tert-butyl 3-(4-propylphenyl)azetidine-1-carboxylate (109 mg, 0.396
mmol) in DCM (1.6 mL) was added TFA (0.4 mL). After 16 h, the
mixture was diluted with DCM (5 mL) and saturated aqueous
NaHCO.sub.3 (10 mL) and allowed to stir for 10 min. The organics
were split off through a hydrophobic frit and evaporated to afford
79 mg (73%) of 3-(4-propylphenyl)azetidine. LCMS-ESI (m/z)
calculated for C.sub.12H.sub.17N: 175.1; found 176.1 [M+H].sup.+,
t.sub.R=1.17 min (Method 11).
Compound 1502 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
3-(4-propylphenyl)azetidine using General Procedure 11.
3-(4-butylphenyl)azetidine
##STR00395##
Following an analogous sequence to that described for the
preparation of 3-(4-propylphenyl)azetidine, tert-butyl
3-oxoazetidine-1-carboxylate and 4-butylphenyl boronic acid gave
3-(4-butylphenyl)azetidine. LCMS-ESI (m/z) calculated for
C.sub.13H.sub.19N: 189.2; found 190.2 [M+H].sup.+, t.sub.R=1.38 min
(Method 11).
Compound 1503 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
3-(4-butylphenyl)azetidine using General Procedure 11.
3-(4-propylphenyl)pyrrolidine
##STR00396##
Following an analogous sequence to that described for the
preparation of 3-(4-propylphenyl)azetidine, tert-butyl
3-oxopyrrolidine-1-carboxylate and 4-propylphenyl boronic acid gave
3-(4-propylphenyl)pyrrolidine. LCMS-ESI (m/z) calculated for
C.sub.13H.sub.19N: 189.2; found 190.2 [M+H].sup.+, t.sub.R=1.27 min
(Method 11).
Compound 1504 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
3-(4-propylphenyl)pyrrolidine using General Procedure 11.
3-(4-butylphenyl)pyrrolidine
##STR00397##
Following an analogous sequence to that described for the
preparation of 3-(4-propylphenyl)azetidine, tert-butyl
3-oxopyrrolidine-1-carboxylate and 4-butylphenyl boronic acid gave
3-(4-butylphenyl)pyrrolidine. LCMS-ESI (m/z) calculated for
C.sub.14H.sub.21N: 203.2; found 204.2 [M+H].sup.+, t.sub.R=1.45 min
(Method 11).
Compound 1505 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
3-(4-butylphenyl)pyrrolidine using General Procedure 11.
benzyl 4-((3-methoxy-3-oxopropyl)amino)piperidine-1-carboxylate
##STR00398##
Prepared using General Procedure 15. To a stirring solution of
glycine methyl ester HCl (2.5 g, 17.91 mmol) in DCM (150 mL) and
MeOH (75 mL) was added benzyl 4-oxopiperidine-1-carboxylate (8.36
g, 35.8 mmol). After 5 min, NaBH(OAc).sub.3 (5.69 g, 26.9 mmol) was
added. After 16 h, solvents were evaporated and the residue taken
into water (50 mL) and extracted with DCM (50 mL then 2.times.10
mL). The combined organic extracts were dried over MgSO.sub.4 and
solvent evaporated. Column chromatography (EA/iso-hexanes) gave 4 g
(70%) of benzyl
4-((3-methoxy-3-oxopropyl)amino)piperidine-1-carboxylate yield) as
a glassy solid. LCMS-ESI (m/z) calculated for
C.sub.17H.sub.24N.sub.2O.sub.4: 320.2; found 321.3 [M+H].sup.+,
t.sub.R=0.97 min (Method 11).
benzyl
4-(3-methoxy-N-(3-methoxy-3-oxopropyl)-3-oxopropanamido)piperidine--
1-carboxylate
##STR00399##
Prepared using General Procedure 3. To a stirring solution of
benzyl 4-((3-methoxy-3-oxopropyl)amino)piperidine-1-carboxylate
(2.74 g, 8.55 mmol) in DCM (100 mL) was added TEA (3 ml, 21.4 mmol)
then methyl 3-chloro-3-oxopropanoate (1.8 ml, 17.1 mmol). After 16
h, the reaction was quenched with water (50 mL) and extracted with
DCM (3.times.50 mL). The combined organic extracts were dried over
MgSO.sub.4 and solvents evaporated. Column chromatography
(EA/iso-hexanes) gave 2.5 g (69%) of benzyl
4-(3-methoxy-N-(3-methoxy-3-oxopropyl)-3-oxopropanamido)piperidine-
-1-carboxylate as a colourless oil. LCMS-ESI (m/z) calculated for
C.sub.21H.sub.28N.sub.2O.sub.7: 420.2; found 421.5 [M+H].sup.+,
t.sub.R=1.96 min (Method 11).
1'-benzyl 3-methyl
2,4-dioxo-[1,4'-bipiperidine]-1',3-dicarboxylate
##STR00400##
To a stirring solution of benzyl
4-(3-methoxy-N-(3-methoxy-3-oxopropyl)-3-oxopropanamido)piperidine-1-carb-
oxylate (3.7 g, 8.80 mmol) in THF (150 mL) was added potassium
tert-butoxide (1.086 g, 9.68 mmol) and the resulting mixture heated
under reflux. After 4 h, the mixture was allowed to cool and poured
into water (70 mL) and extracted with EA (3.times.85 mL). The
combined organic extracts were dried over MgSO.sub.4 and solvents
evaporated. Column chromatography (EA/iso-hexanes) gave 2 g (58%)
of 1'-benzyl 3-methyl
2,4-dioxo-[1,4'-bipiperidine]-1',3-dicarboxylate as a colourless
oil. LCMS-ESI (m/z) calculated for C.sub.20H.sub.24N.sub.2O.sub.6:
388.2; found 389.5 [M+H].sup.+, t.sub.R=1.96 min (Method 11).
benzyl 2,4-dioxo-[1,4'-bipiperidine]-1'-carboxylate
##STR00401##
To a stirring solution of oxalic acid (1062 mg, 11.80 mmol) in
water (12 mL) was added 1'-benzyl 3-methyl
2,4-dioxo-[1,4'-bipiperidine]-1',3-dicarboxylate (2.2 g, 5.90 mmol)
and the resulting mixture heated at 100.degree. C. for 4 h. The
reaction mixture was allowed to cool and extracted with EA
(3.times.150 mL). The combined organic layers were dried over
MgSO.sub.4 and solvents evaporated. Column chromatography
(EA/iso-hexanes) gave 0.8 g (41%) of benzyl
2,4-dioxo-[1,4'-bipiperidine]-1'-carboxylate as a colourless oil.
LCMS-ESI (m/z) calculated for C.sub.18H.sub.22N.sub.2O.sub.4:
330.2; found 331.5 [M+H].sup.+, t.sub.R=1.69 min (Method 11).
benzyl
4-(4-bromo-2-oxo-5,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxyla-
te
##STR00402##
To a stirring solution of DMF (0.64 ml, 8.27 mmol) in DCM (10 mL)
at 0.degree. C. was added oxalyl bromide (0.41 ml, 4.36 mmol). When
gas evolution was observed to have ceased, a solution of benzyl
2,4-dioxo-[1,4'-bipiperidine]-1'-carboxylate (0.6 g, 1.816 mmol) in
DCM (10 mL) was added and the resulting reaction was stirred at
0.degree. C. for 1 h and then for a further 1 h at ambient
temperature. The reaction was poured into ice-water (10 mL) and
extracted with DCM (2.times.15 mL). The combined organic layers
were dried over MgSO.sub.4 and solvents evaporated. Column
chromatography on companion (40 g column, 0-100% EA/iso-hexanes)
gave 0.4 g (56%) benzyl
4-(4-bromo-2-oxo-5,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxylate
as a yellow oil. LCMS-ESI (m/z) calculated for
C.sub.18H.sub.21BrN.sub.2O.sub.3: 392.1; found 393.3 [M+H].sup.+,
t.sub.R=2.15 min (Method 11).
benzyl
4-(4-butyl-2-oxo-5,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxyla-
te
##STR00403##
To a stirring solution of Pd.sub.2dba.sub.3 (46.6 mg, 0.051 mmol)
and RuPhos (95 mg, 0.203 mmol) in DMA (2 mL) was added benzyl
4-(4-bromo-2-oxo-5,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxylate
(400 mg, 1.017 mmol) to afford a bromide solution. Meanwhile, in a
separate vessel, a stirring suspension of ZnCl.sub.2. TMEDA (513
mg, 2.034 mmol) in Et.sub.2O (4 mL) at 0.degree. C. was treated
with butyllithium (0.8 ml of a 2.5 M solution in hexanes, 2 mmol).
This mixture was allowed to warm to ambient temperature and then
stirred for a further 15 min to afford an organozinc solution. The
organozinc solution was added via cannula to the bromide solution.
After 14 h, solvents were evaporated and the residue purified by
column chromatography to afford 377 mg (100%) of benzyl
4-(4-butyl-2-oxo-5,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxylate.
LCMS-ESI (m/z) calculated for C.sub.22H.sub.30N.sub.2O.sub.3:
370.2; found 371.3 [M+H].sup.+, t.sub.R=2.37 min (Method 11).
4-butyl-[1,4'-bipiperidin]-2-one
##STR00404##
Prepared using General Procedure 18. To a stirring solution of
benzyl
4-(4-butyl-2-oxo-5,6-dihydropyridin-1(2H)-yl)piperidine-1-carboxylate
(400 mg, 1.080 mmol) in MeOH (30 mL) was added Pd/C (34.5 mg,
Johnson and Matthey Type 39 Paste). The mixture was hydrogenated
under 5 bar. After 16 h, the mixture was filtered through Celite
and solvents evaporated to give 140 mg (54%) of
4-butyl-[1,4'-bipiperidin]-2-one as a colourless oil. LCMS-ESI
(m/z) calculated for C.sub.14H.sub.26N.sub.2O: 238.2; found 239.4
[M+H].sup.+, t.sub.R=1.16 min (Method 11).
Compound 1506 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
4-butyl-[1,4'-bipiperidin]-2-one using General Procedure 11.
4-(4-propylphenyl)azepane
##STR00405##
Following an analogous sequence to that described for the
preparation of 3-(4-propylphenyl)azetidine, tert-butyl
4-oxoazepane-1-carboxylate and 4-propylphenyl boronic acid gave
4-(4-propylphenyl)azepane. LCMS-ESI (m/z) calculated for
C.sub.15H.sub.23N: 217.2; found 218.2 [M+H].sup.+, t.sub.R=1.47 min
(Method 11).
Compound 1507 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
4-(4-propylphenyl)azepane using General Procedure 11.
4-(4-butylphenyl)azepane
##STR00406##
Following an analogous sequence to that described for the
preparation of 3-(4-propylphenyl)azetidine, tert-butyl
4-oxoazepane-1-carboxylate and 4-butylphenyl boronic acid gave
4-(4-butylphenyl)azepane. LCMS-ESI (m/z) calculated for
C.sub.15H.sub.23N: 231.2; found 232.2 [M+H].sup.+, t.sub.R=1.38 min
(Method 11).
Compound 1508 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
4-(4-butylphenyl)azepane using General Procedure 11.
3-(4-propylbenzyl)azetidine
##STR00407##
Following an analogous sequence to that described for the
preparation of 3-(4-propylphenyl)azetidine, tert-butyl
3-formylazetidine-1-carboxylate and 4-propylphenyl boronic acid
gave 3-(4-propylbenzyl)azetidine. LCMS-ESI (m/z) calculated for
C.sub.13H.sub.19N: 189.2; found 190.1 [M+H].sup.+, t.sub.R=1.32 min
(Method 11).
Compound 1509 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
3-(4-propylbenzyl)azetidine using General Procedure 11.
3-(4-butylbenzyl)azetidine
##STR00408##
Following an analogous sequence to that described for the
preparation of 3-(4-propylphenyl)azetidine, tert-butyl
3-formylazetidine-1-carboxylate and 4-butylphenyl boronic acid gave
3-(4-butylbenzyl)azetidine. LCMS-ESI (m/z) calculated for
C.sub.13H.sub.19N: 203.2; found 204.2 [M+H].sup.+, t.sub.R=1.48 min
(Method 11).
Compound 1510 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
3-(4-butylbenzyl)azetidine using General Procedure 11.
1-(4-propylphenyl)piperazine
##STR00409##
Prepared using General Procedure 11. To a stirring solution of
1-bromo-4-propylbenzene (0.389 ml, 2.51 mmol) in toluene (12 mL)
was added piperazine (281 mg, 3.26 mmol) and sodium tert-butoxide
(965 mg, 10.05 mmol). The mixture was de-gassed then treated with
BINAP (156 mg, 0.251 mmol) and Pd.sub.2(dba).sub.3 (115 mg, 0.126
mmol) then heated to 100.degree. C. After 16 h, the mixture was
allowed to cool then poured onto 1 M HCl (5 mL) and extracted with
EA (3.times.10 mL). The combined organic layers were washed with
brine (10 mL), dried over MgSO.sub.4 and solvents evaporated.
Column chromatography (NH.sub.3/MeOH/DCM) gave 261 mg (51%) of
1-(4-propylphenyl)piperazine as a dark brown gum. LCMS-ESI (m/z)
calculated for C.sub.13H.sub.20N.sub.2: 204.2; found 205.2
[M+H].sup.+, t.sub.R=1.26 min (Method 11).
Compound 1511 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
1-(4-propylphenyl)piperazine using General Procedure 11.
((1s,4r)-4-propylcyclohexyl)methanol
##STR00410##
To a stirring solution of (1s,4r)-4-propylcyclohexanecarboxylic
acid (10 g, 58.2 mmol) and TEA (9.40 ml, 67.5 mmol) in THF (100 mL)
at 0.degree. C. was added iso-butyl chloroformate (8.86 ml, 67.5
mmol). After 1 h, the precipitate was removed by filtration,
washing through with further THF (40 mL). The combined THF solution
was recooled to 0.degree. C. with stirring and a solution of
NaBH.sub.4 (11.00 g, 291 mmol) in water (130 mL) added slowly.
After 45 min, the reaction was diluted with EA (200 mL) and washed
successively with saturated aqueous NH.sub.4Cl (100 mL), saturated
aqueous NaHCO.sub.3 (100 mL) and brine (100 mL), dried over
MgSO.sub.4 and evaporated. Column chromatography
(Et.sub.2O/iso-hexanes) gave 7.6 g (83%) of
((1s,4r)-4-propylcyclohexyl)methanol as a colourless oil. LCMS-ESI
(m/z) calculated for C.sub.10H.sub.20O: 156.2: no response observed
(Method 11). .sup.1H NMR (400 MHz, Chloroform-d) .delta. 3.38 (d,
J=6.4 Hz, 2H), 1.83-1.63 (m, 4H), 1.41-1.34 (m, 1H), 1.30-1.19 (m,
2H), 1.18-1.02 (m, 3H), 0.96-0.71 (m, 7H).
(E)-methyl 3-((1s,4r)-4-propylcyclohexyl)acrylate
##STR00411##
To a stirring solution of ((1s,4r)-4-propylcyclohexyl)methanol (7.6
g, 48.6 mmol) in DCM (250 mL) was added Dess-Martin Periodinane
(22.69 g, 53.5 mmol). After 1 h, saturated aqueous sodium
thiosulfate (20 mL) was added. After 5 min, water (50 mL) was added
and the layers separated. The organic phase was washed successively
with saturated aqueous NaHCO.sub.3 (100 mL) and brine (100 mL) and
dried over MgSO.sub.4. This solution was then stirred with methyl
2-(triphenylphosphoranylidene)acetate (22.76 g, 68.1 mmol). After
16 h, solvents were evaporated and the residue purified by column
chromatography (EA/iso-hexanes) to afford 4.85 g (47%) of
(E)-methyl 3-((1s,4r)-4-propylcyclohexyl)acrylate as a yellow oil.
LCMS-ESI (m/z) calculated for C.sub.13H.sub.22O.sub.2: 210.2; found
211.2 [M+H].sup.+, t.sub.R=3.04 min (Method 11).
dimethyl 3-((1 s,4r)-4-propylcyclohexyl)pentanedioate
##STR00412##
To a stirred solution of DIEA (3.68 ml, 25.8 mmol) in THF (50 mL)
at -78.degree. C. was added butyllithium (10.3 mL of a 2.5 M
solution in hexanes, 25.8 mmol). The resultant solution was stirred
for 15 min whereupon methyl acetate (2.1 mL, 25.8 mmol) was added.
After 30 min, a solution of (E)-methyl
3-((1s,4r)-4-propylcyclohexyl)acrylate (4.52 g, 21.49 mmol) in THF
(2 mL) was added and the mixture allowed to warm slowly. After 72
h, the reaction was quenched into 1 M HCl (100 mL) and extracted
with Et.sub.2O (3.times.100 mL). The combined organics were washed
with brine (100 mL), dried over MgSO.sub.4 and solvents evaporated.
The residue was purified by column chromatography (EA/iso-hexanes)
to afford 0.82 g (13%) of dimethyl
3-((1s,4r)-4-propylcyclohexyl)pentanedioate as a colourless oil.
LCMS-ESI (m/z) calculated for C.sub.16H.sub.28O.sub.4: 284.2; found
285.3 [M+H].sup.+, t.sub.R=2.94 min (Method 11).
4-((1 s,4r)-4-propylcyclohexyl)dihydro-2H-pyran-2,6(3H)-dione
##STR00413##
To a stirring solution of dimethyl
3-((1s,4r)-4-propylcyclohexyl)pentanedioate (310 mg, 1.090 mmol) in
THF (5 mL) and water (5 mL) was added lithium hydroxide (261 mg,
10.90 mmol). After 16 h, the reaction mixture was quenched into 1 M
HCl (30 mL) and extracted with EA (3.times.30 mL). The combined
organic layers were washed with brine (30 mL), dried over
MgSO.sub.4 and solvents evaporated. The residue was dissolved in
acetic anhydride (10 mL) with stirring and heated under reflux.
After 3 h, solvents were evaporated, chasing off with toluene
(2.times.10 mL) to afford 272 mg (100%) of
4-((1s,4r)-4-propylcyclohexyl)dihydro-2H-pyran-2,6(3H)-dione.
LCMS-ESI (m/z): calculated for C.sub.14H.sub.22O.sub.3: 238.2 no
response observed (Method 11). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 2.81-2.71 (m, 2H), 2.63-2.53 (m, 2H), 2.05-1.96 (m, 1H),
1.78-1.59 (m, 4H), 1.33-1.22 (m, 2H), 1.19-1.07 (m, 4H), 0.98-0.77
(m, 7H).
Compound 1512 was prepared from
(S)-1-(3-(4-(5-bromopyrimidin-2-yl)phenyl)-2-(5-(tert-butyl)thiophene-2-c-
arboxamido)propanoyl)azetidine-3-carboxylic acid (INT-71) and
tert-butyl carbamate using General Procedures 11 and 8 sequentially
and then using
4-((1s,4r)-4-propylcyclohexyl)dihydro-2H-pyran-2,6(3H)-dione and
General Procedure 7.
(S)-methyl
1-(2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoyl)-
-azetidine-3-carboxylate
##STR00414##
Prepared using General Procedure 7. To a stirring solution of
methyl azetidine-3-carboxylate hydrochloride (14.42 g, 95 mmol),
DIEA (33.2 mL, 190 mmol) and
(S)-2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoic
acid (10 g, 31.7 mmol) in DMF (200 mL) at 0.degree. C. was added
HATU (13.26 g, 34.9 mmol) portionwise. After 30 min, additional
HATU (6.03 g, 15.86 mmol) was added. After a further 30 min,
additional HATU (6.03 g, 15.86 mmol) was added. After a further 30
min, additional HATU (6.03 g, 15.86 mmol) was added. The mixture
was poured into 1 M HCl (200 mL) and extracted with EA (2.times.300
mL). The combined organic extracts were washed with brine
(2.times.200 mL), dried over MgSO.sub.4 and solvents evaporated to
afford 13.08 g (100%) of (S)-methyl
1-(2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoyl)azetidine--
3-carboxylate. LCMS-ESI (m/z) calculated for
C.sub.22H.sub.24N.sub.2O.sub.6: 412.2; found 413.2 [M+H].sup.+,
t.sub.R=1.76 min (Method 11).
(S)-methyl
1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfo-
nyl)-oxy)phenyl)propanoyl)azetidine-3-carboxylate
##STR00415##
Prepared using General Procedure 9. To a stirring solution of
1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide
(11.33 g, 31.7 mmol) and (S)-methyl
1-(2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoyl)azetidine--
3-carboxylate (13.08 g, 31.7 mmol) in DCM (300 mL) was added DIEA
(5.54 ml, 31.7 mmol). After 16 h, additional
1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide
(2.266 g, 6.34 mmol) was added. After a further 5 h, the mixture
was washed successively with 1 M HCl (300 mL), saturated aqueous
NaHCO.sub.3 (300 mL) and brine (300 mL). The organic phase was
dried over MgSO.sub.4 and solvent evaporated. Column chromatography
(EA/DCM/iso-hexanes) gave 17.2 g (100%) of (S)-methyl
1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)ph-
enyl)propanoyl)azetidine-3-carboxylate (11.2 g, 19.54 mmol, 61.6%
yield) as a thick orange oil. LCMS-ESI (m/z) calculated for
C.sub.23H.sub.23F.sub.3N.sub.2O.sub.8S: 544.1; found 545.1
[M+H].sup.+, t.sub.R=2.40 min (Method 11).
(S)-methyl
1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3-
,2-dioxaborolan-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
##STR00416##
Prepared using General Procedure 27. To a stirring solution of
(S)-methyl
1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(((trifluoromethyl)sulfonyl)oxy)ph-
enyl)propanoyl)-azetidine-3-carboxylate (18.1 g, 31.6 mmol) and
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (8.02
g, 31.6 mmol) in dioxane (200 mL) was added potassium acetate (9.30
g, 95 mmol) and the mixture de-gassed. PdCl.sub.2dppf (1.155 g,
1.579 mmol) was charged and the mixture heated to 100.degree. C.
After 4 h, the mixture was allowed to cool then treated with a
mixture of water (300 mL) and brine (200 mL) and extracted with EA
(400 mL then 2.times.300 mL). The combined organic layers were
dried over MgSO.sub.4 and solvents evaporated. Column
chromatography (EA/DCM/iso-hexanes) gave 15 g (91%) of (S)-methyl
1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl)propanoyl)azetidine-3-carboxylate as a yellow
oil. LCMS-ESI (m/z) calculated for C.sub.28H.sub.35BN.sub.2O.sub.7:
544.1; found 545.1 [M+H].sup.+, t.sub.R=2.40 min (Method 11).
1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1s,4r)-4-propylcyclohex-
yl)-piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic
acid
##STR00417##
Prepared using General Procedure 10. To a stirring mixture of
2-chloro-5-(4-((1s,4r)-4-propylcyclohexyl)piperidin-1-yl)pyrimidine
(INT-80) (310 mg, 0.963 mmol) and (S)-methyl
1-(2-(((benzyloxy)carbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (503 mg, 0.963
mmol) in dioxane (3 mL) and toluene (3 mL) was added solid
NaHCO.sub.3 (324 mg, 3.85 mmol) and water (2 mL). The mixture was
de-gassed then treated with PdCl.sub.2(dppf) (49.3 mg, 0.067 mmol)
and heated to 100.degree. C. After 7 h, the reaction mixture was
allowed to cool then diluted with EA (50 mL) and washed with brine
(30 mL). The organics were dried MgSO.sub.4 and solvents
evaporated. Column chromatography (DCM/THF) gave 427 mg (66%) of
1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1s,4r)-4-propylcyclohe-
xyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic
acid as a tan solid. LCMS-ESI (m/z) calculated for
C.sub.39H.sub.49N.sub.5O.sub.5: 667.4; found 668.4 [M+H].sup.+,
t.sub.R=3.21 min (Method 11).
methyl
1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1s,4r)-4-propylc-
yclohexyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carbo-
xylate
##STR00418##
To a stirring solution of
1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1s,4r)-4-propylcyclohe-
xyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic
acid (427 mg, 0.639 mmol) in THF (3 mL) was added MeOH (0.6 mL) and
water (0.6 mL). (Diazomethyl)trimethylsilane (448 .mu.L of a 2 M
solution in Et.sub.2O, 0.895 mmol) was added dropwise. After 1 h,
solvents were evaporated and the residue purified by column
chromatography (DCM/THF) to afford 360 mg (83%) of
1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1s,4r)-4-propylcyclohe-
xyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
as an orange solid. LCMS-ESI (m/z) calculated for
C.sub.40H.sub.51N.sub.5O.sub.5: 681.4; found 682.4 [M+H].sup.+,
t.sub.R=3.29 min (Method 11).
methyl
1-((S)-2-amino-3-(4-(5-(4-((1s,4r)-4-propylcyclohexyl)piperidin-1-y-
l)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
(INT-82)
##STR00419##
Prepared using General Procedure 18. To a stirring solution of
methyl
1-((S)-2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-((1s,4r)-4-propylcyclohe-
xyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate
(350 mg, 0.513 mmol) in THF (4 mL) was added Pd/C (137 mg of
Johnson and Matthey Type 39 paste) and the mixture hydrogenated
under 5 bar. After 7 h, the mixture was filtered through Celite,
washing with EA (3.times.30 mL). Solvents were evaporated to afford
234 mg (81%) of
1-((S)-2-amino-3-(4-(5-(4-((1s,4r)-4-propylcyclohexyl)piperidin-1-yl)pyri-
midin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (INT-82) as a
white solid. LCMS-ESI (m/z) calculated for
C.sub.32H.sub.45N.sub.5O.sub.3: 547.4; found 548.4 [M+H].sup.+,
t.sub.R=2.24 min (Method 11).
Compounds 1513-1538 were prepared from methyl
1-((S)-2-amino-3-(4-(5-(4-((1s,4r)-4-propylcyclohexyl)piperidin-1-yl)pyri-
midin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (INT-82) using
General Procedures 7 and 4 sequentially.
Compounds 1539-1550 were prepared from
(S)-2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-((1s,4r)-4-propy-
lcyclohexyl)piperidin-1-yl)pyrimidin-2-yl)phenyl)propanoic acid
(Compound 1439) using General Procedure 7.
Compound 1551 was prepared from
(S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,3,4-thiad-
iazol-2-yl)phenyl)propanoic acid (Compound 83) using General
Procedures 7 then 8.
tert-butyl 2-(4-(heptyloxy)benzoyl)hydrazinecarboxylate
##STR00420##
Prepared using General Procedure 3. To a stirring suspension of
4-(heptyloxy)benzoic acid (2.516 g, 10.65 mmol) in DCM (20 mL) was
added DMF (1 drop) then oxalyl chloride (1.1 mL, 12.78 mmol). After
2 h, this solution was evaporated and the residue taken up in DCM
(5 mL). This solution was then added dropwise to a stirring
solution of tert-butyl hydrazinecarboxylate (1.548 g, 11.71 mmol)
and DIEA (3.0 mL, 15.97 mmol) in DCM (20 mL) at 5.degree. C. such
that the internal temperature was maintained between 5.degree. C.
and 10.degree. C. After a further 1 h at this temperature, the
mixture was poured onto 1 M HCl (50 mL) and extracted with EA
(3.times.30 mL). The combined organic extracts were washed
successively with saturated aqueous NaHCO.sub.3 (30 mL) and brine
(20 mL), dried over MgSO.sub.4 and evaporated to afford 3.66 g
(98%) of tert-butyl 2-(4-(heptyloxy)benzoyl)hydrazinecarboxylate as
an off-white solid. LCMS-ESI (m/z) calculated for
C.sub.19H.sub.30N.sub.2O.sub.4: 350.2; found 373.1 [M+Na].sup.+,
t.sub.R=2.65 min (Method 11).
tert-butyl
2-(4-(heptyloxy)phenylcarbonothioyl)hydrazinecarboxylate
##STR00421##
To a stirring solution of tert-butyl
2-(4-(heptyloxy)benzoyl)hydrazinecarboxylate (2.62 g, 7.48 mmol) in
THF (35 mL) was added
2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide
(3.18 g, 7.85 mmol) and the mixture heated under reflux. After 2 h,
the mixture was allowed to cool then filtered, washing with THF
(2.times.10 mL). The filtrate was evaporated onto silica and
directly purified by column chromatography
(Et.sub.2O/DCM/iso-hexanes) to afford 1.91 g (69%) of tert-butyl
2-(4-(heptyloxy)phenylcarbonothioyl)hydrazinecarboxylate as a
yellow oil. LCMS-ESI (m/z) calculated for
C.sub.19H.sub.30N.sub.2O.sub.3S: 366.2; found 389.0 [M+Na].sup.+,
t.sub.R=2.05 min (Method 11).
4-(heptyloxy)benzothiohydrazide hydrochloride
##STR00422##
Prepared using General Procedure 8. To a stirring solution of
tert-butyl 2-(4-(heptyloxy)phenylcarbonothioyl)hydrazinecarboxylate
(1.8 g, 4.91 mmol) in DCM (10 mL) was added hydrogen chloride (4 M
in dioxane) (24.6 mL of a 4 M solution in dioxane, 98 mmol). After
2 h, the mixture was treated with iso-hexanes (30 mL) and stirred
for 1 h. The product was collected by filtration, washing with
iso-hexanes (5 mL) to afford 1.06 g (71%) of
4-(heptyloxy)benzothiohydrazide hydrochloride as a yellow
micro-crystalline solid. LCMS-ESI (m/z) calculated for
C.sub.14H.sub.22N.sub.2O.sub.2S: 266.2; found 267.0 [M+H].sup.+,
t.sub.R=2.50 min (Method 11).
2-(4-bromo-2-fluorophenyl)-5-(4-(heptyloxy)phenyl)-1,3,4-thiadiazole
##STR00423##
To a stirred solution of 4-bromo-2-fluorobenzoic acid (240 mg,
1.096 mmol) in NMP (4 mL) was added DIEA (0.5 ml, 2.74 mmol) and
HATU (438 mg, 1.151 mmol). After 10 min,
4-(heptyloxy)benzothiohydrazide hydrochloride (332 mg, 1.096 mmol)
was added. After 1 h, hydrogen chloride (2.7 mL of a 4 M solution
in dioxanes, 10.96 mmol) was added and the mixture heated to
60.degree. C. After 1 h, the mixture was allowed to cool then
treated with water (8 mL) and ACN (4 mL) and stirred for 1 h. The
product was collected by filtration, washing successively with
water (3.times.5 mL) then ACN (2.times.2 mL) to afford 390 mg (79%)
of
2-(4-bromo-2-fluorophenyl)-5-(4-(heptyloxy)phenyl)-1,3,4-thiadiazole.
LCMS-ESI (m/z) calculated for C.sub.21H.sub.22BrFN.sub.2OS: 448.1;
found 448.8 [M+H].sup.+, t.sub.R=3.29 min (Method 11).
(S)-methyl
2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-(5-(4-(heptyloxy)p-
henyl)-1,3,4-thiadiazol-2-yl)phenyl)propanoate
##STR00424##
Prepared using General Procedure 31. To a stirring suspension of
zinc (109 mg, 1.669 mmol) in DMF (2 mL) was added iodine (21 mg,
0.083 mmol). After the colour was observed to have been discharged,
(R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (183 mg,
0.556 mmol) and further iodine (21 mg, 0.083 mmol) were charged.
After a further 30 min, the mixture was treated with
2-(4-bromo-2-fluorophenyl)-5-(4-(heptyloxy)phenyl)-1,3,4-thiadiazole
(250 mg, 0.556 mmol), diluted with DMF (1 mL) and de-gassed. The
mixture was treated with
dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (11 mg,
0.028 mmol) and Pd.sub.2dba.sub.3 (13 mg, 0.014 mmol) then heated
to 50.degree. C. After 3 h, the mixture was allowed to cool then
directly purified by column chromatography (EA/iso-hexanes) to
afford 238 mg (75%) of (S)-methyl
2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-(5-(4-(heptyloxy)phenyl)-1,3-
,4-thiadiazol-2-yl)phenyl)propanoate as a waxy, yellow solid.
LCMS-ESI (m/z) calculated for C.sub.30H.sub.38FN.sub.3O.sub.5S:
571.3; found 572.2 [M+H].sup.+, t.sub.R=3.00 min (Method 11).
(S)-methyl
2-(4-(tert-butyl)benzamido)-3-(3-fluoro-4-(5-(4-(heptyloxy)phen-
yl)-1,3,4-thiadiazol-2-yl)phenyl)propanoate
##STR00425##
Prepared using General Procedures 8 and 7 sequentially. To a
stirring solution of (S)-methyl
2-((tert-butoxycarbonyl)amino)-3-(3-fluoro-4-(5-(4-(heptyloxy)phenyl)-1,3-
,4-thiadiazol-2-yl)phenyl)propanoate (194 mg, 0.339 mmol) in DCM (2
mL) was added TFA (2 mL). After 1 h, the mixture was diluted with
toluene (2 mL) and solvents evaporated. The residue was taken up in
DCM (4 mL) and shaken with saturated aqueous NaHCO.sub.3 (15 mL).
The organics were split off through a hydrophobic frit directly
into a stirring solution of 4-(tert-butyl)benzoic acid (66.5 mg,
0.373 mmol), DIEA (157 .mu.l, 0.848 mmol) and HATU (135 mg, 0.356
mmol) in DMF (2 mL). After 16 h, the mixture was diluted with DCM
(3 mL) and stirred with saturated aqueous NaHCO.sub.3 (15 mL) for
15 min. The organics were split off through a hydrophobic frit and
solvents evaporated. Column chromatography (EA/DCM/iso-hexanes)
gave 186 mg (87%) of (S)-methyl
2-(4-(tert-butyl)benzamido)-3-(3-fluoro-4-(5-(4-(heptyloxy)phenyl)-1,3,4--
thiadiazol-2-yl)phenyl)propanoate as an off-white flaky solid.
LCMS-ESI (m/z) calculated for C.sub.36H.sub.42FN.sub.3O.sub.4S:
631.3; found 632.3 [M+H].sup.+, t.sub.R=3.15 min (Method 11).
(S)-2-(4-(tert-butyl)benzamido)-3-(3-fluoro-4-(5-(4-(heptyloxy)phenyl)-1,3-
,4-thiadiazol-2-yl)phenyl)propanoic acid (Compound 1552)
##STR00426##
Prepared using General Procedure 4. To a stirring solution of
(S)-methyl
2-(4-(tert-butyl)benzamido)-3-(3-fluoro-4-(5-(4-(heptyloxy)phenyl)-1,3,4--
thi adiazol-2-yl)phenyl)propanoate (165 mg, 0.261 mmol) in THF (5
mL) and MeOH (2 mL) was added lithium hydroxide (522 .mu.l of a 1 M
aqueous solution, 0.522 mmol). After 18 h, the mixture was quenched
with AcOH (150 .mu.l, 2.61 mmol) then treated with water (15 mL)
and stirred for 1 h. The product was collected by filtration,
washing successively with water (2.times.5 mL) and ACN (2.times.2
mL) to afford 160 mg (99%) of
(S)-2-(4-(tert-butyl)benzamido)-3-(3-fluoro-4-(5-(4-(heptyloxy)phenyl)-1,-
3,4-thiadiazol-2-yl)phenyl)propanoic acid (Compound 1552) as a
white solid. LCMS-ESI (m/z) calculated for
C.sub.35H.sub.40FN.sub.3O.sub.4S: 617.3; found 618.3 [M+H].sup.+,
t.sub.R=10.98 min (Method 10). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.90 (s, 1H), 8.71 (d, J=8.3 Hz, 1H), 8.19 (t, J=7.9 Hz,
1H), 8.05-7.87 (m, 2H), 7.83-7.66 (m, 2H), 7.57-7.43 (m, 3H), 7.38
(dd, J=8.2, 1.6 Hz, 1H), 7.19-7.01 (m, 2H), 4.73 (ddd, J=10.7, 8.2,
4.5 Hz, 1H), 4.05 (t, J=6.5 Hz, 2H), 3.35-3.30 (m, 1H), 3.18 (dd,
J=13.8, 10.8 Hz, 1H), 1.87-1.64 (m, 2H), 1.46-1.27 (m, 17H),
0.97-0.74 (m, 3H).
Compound 1553 was prepared from
(R)-2-(4-(tert-butyl)benzamido)-3-(3-fluoro-4-(5-(4-(heptyloxy)phenyl)-1,-
3,4-thiadiazol-2-yl)phenyl)propanoic acid (Compound 1552) using
General Procedures 7 then 8.
Selected compounds and their corresponding analytical data are
shown in Table 1, where the LCMS data was collected using the
method indicated.
TABLE-US-00001 TABLE 1 Representative Compounds COM- LCMS POUND
RETENTION PURITY STRUCTURE NUMBER TIME (min) METHOD ##STR00427## 1
12.42 2 ##STR00428## 2 12.17 2 ##STR00429## 3 11.65 2 ##STR00430##
4 11.13 2 ##STR00431## 5 10.65 2 ##STR00432## 6 11.66 2
##STR00433## 7 10.04 2 ##STR00434## 8 10.92 2 ##STR00435## 9 9.58 2
##STR00436## 10 10.69 2 ##STR00437## 11 10.13 2 ##STR00438## 13
11.46 2 ##STR00439## 14 11.45 2 ##STR00440## 15 10.95 2
##STR00441## 16 11.55 2 ##STR00442## 17 11.04 2 ##STR00443## 18
10.66 2 ##STR00444## 19 10.69 2 ##STR00445## 20 10.78 2
##STR00446## 21 10.74 2 ##STR00447## 22 10.75 2 ##STR00448## 23
10.66 2 ##STR00449## 24 10.72 2 ##STR00450## 25 10.50 2
##STR00451## 26 10.53 2 ##STR00452## 27 11.48 2 ##STR00453## 28
10.05 2 ##STR00454## 29 10.07 2 ##STR00455## 30 10.03 2
##STR00456## 31 9.83 2 ##STR00457## 32 10.77 2 ##STR00458## 33
10.75 2 ##STR00459## 34 11.00 2 ##STR00460## 35 11.09 2
##STR00461## 36 9.19 2 ##STR00462## 37 10.98 2 ##STR00463## 38 9.93
2 ##STR00464## 39 9.30 2 ##STR00465## 40 9.87 2 ##STR00466## 41
8.29 2 ##STR00467## 42 10.32 2 ##STR00468## 43 8.20 2 ##STR00469##
44 8.14 2 ##STR00470## 45 9.29 2 ##STR00471## 46 11.40 2
##STR00472## 47 10.07 2 ##STR00473## 48 10.38 2 ##STR00474## 49
9.78 2 ##STR00475## 50 9.79 2 ##STR00476## 51 11.93 2 ##STR00477##
52 10.36 2 ##STR00478## 53 10.23 2 ##STR00479## 54 7.85 2
##STR00480## 55 8.17 2 ##STR00481## 56 10.44 2 ##STR00482## 57
10.46 2 ##STR00483## 58 10.25 2 ##STR00484## 59 10.85 2
##STR00485## 60 10.33 2 ##STR00486## 61 7.66 2 ##STR00487## 62 8.28
2 ##STR00488## 63 9.34 2 ##STR00489## 64 9.05 2 ##STR00490## 65
9.69 2 ##STR00491## 66 6.46 2 ##STR00492## 67 11.51 2 ##STR00493##
68 10.10 2 ##STR00494## 69 11.90 2 ##STR00495## 70 11.67 2
##STR00496## 71 11.05 9 ##STR00497## 72 9.22 9 ##STR00498## 73
11.42 9 ##STR00499## 74 9.61 9 ##STR00500## 75 9.13 9 ##STR00501##
76 10.06 9 ##STR00502## 77 10.87 9 ##STR00503## 78 11.03 9
##STR00504## 79 11.30 9 ##STR00505## 80 11.57 9 ##STR00506## 81
11.23 9 ##STR00507## 82 11.21 9 ##STR00508## 83 10.60 9
##STR00509## 84 11.56 9 ##STR00510## 85 11.18 9 ##STR00511## 86
9.46 9 ##STR00512## 87 10.09 9 ##STR00513## 88 9.51 9 ##STR00514##
89 10.26 9 ##STR00515## 90 10.33 9 ##STR00516## 91 10.64 9
##STR00517## 92 10.48 9 ##STR00518## 93 10.63 9 ##STR00519## 94
10.85 10 ##STR00520## 95 10.58 9 ##STR00521## 96 9.69 9
##STR00522## 97 10.22 9 ##STR00523## 98 9.36 9 ##STR00524## 99 8.75
9 ##STR00525## 100 11.08 9 ##STR00526## 101 10.70 9 ##STR00527##
102 8.51 9 ##STR00528## 104 8.44 9 ##STR00529## 105 9.46 9
##STR00530## 106 11.27 9 ##STR00531## 107 11.13 9 ##STR00532## 108
9.88 9 ##STR00533## 109 9.87 9 ##STR00534## 110 9.90 9 ##STR00535##
111 9.86 9 ##STR00536## 112 11.34 9 ##STR00537## 113 9.19 9
##STR00538## 114 8.49 9 ##STR00539## 115 7.95 9 ##STR00540## 116
11.14 2 ##STR00541## 117 10.15 9 ##STR00542## 118 9.90 9
##STR00543## 119 9.67 9 ##STR00544## 120 10.41 9 ##STR00545## 121
10.86 9 ##STR00546## 122 9.30 9 ##STR00547## 123 9.02 9
##STR00548## 124 10.38 9
##STR00549## 125 10.51 9 ##STR00550## 126 8.38 9 ##STR00551## 127
8.95 9 ##STR00552## 128 8.42 9 ##STR00553## 129 11.13 10
##STR00554## 130 10.23 10 ##STR00555## 131 9.70 10 ##STR00556## 132
10.27 10 ##STR00557## 133 10.87 10 ##STR00558## 134 6.44 10
##STR00559## 135 10.67 10 ##STR00560## 136 9.85 10 ##STR00561## 137
10.48 10 ##STR00562## 138 10.13 10 ##STR00563## 139 9.09 10
##STR00564## 140 10.76 10 ##STR00565## 141 10.83 10 ##STR00566##
142 10.42 10 ##STR00567## 143 9.47 10 ##STR00568## 144 9.83 10
##STR00569## 145 10.79 10 ##STR00570## 146 10.77 10 ##STR00571##
147 10.86 10 ##STR00572## 148 10.17 10 ##STR00573## 149 11.95 2
##STR00574## 150 11.83 2 ##STR00575## 151 12.41 2 ##STR00576## 152
12.06 2 ##STR00577## 153 12.37 2 ##STR00578## 154 11.19 2
##STR00579## 155 11.73 2 ##STR00580## 156 11.40 10 ##STR00581## 157
11.93 2 ##STR00582## 158 11.13 2 ##STR00583## 159 7.23 9
##STR00584## 160 8.85 9 ##STR00585## 161 9.24 9 ##STR00586## 162
8.83 9 ##STR00587## 163 9.78 9 ##STR00588## 164 10.44 2
##STR00589## 165 9.69 10 ##STR00590## 166 8.97 10 ##STR00591## 167
7.54 10 ##STR00592## 168 8.35 10 ##STR00593## 169 9.32 10
##STR00594## 170 8.23 10 ##STR00595## 171 8.67 10 ##STR00596## 172
10.31 10 ##STR00597## 173 9.27 10 ##STR00598## 174 9.17 10
##STR00599## 175 7.34 10 ##STR00600## 176 7.97 10 ##STR00601## 177
8.87 10 ##STR00602## 178 7.94 10 ##STR00603## 179 9.31 10
##STR00604## 180 8.79 10 ##STR00605## 181 8.11 10 ##STR00606## 182
9.75 10 ##STR00607## 183 9.13 9 ##STR00608## 184 10.87 2
##STR00609## 185 11.32 2 ##STR00610## 186 11.02 2 ##STR00611## 187
11.21 2 ##STR00612## 188 11.56 2 ##STR00613## 189 11.25 2
##STR00614## 190 11.42 2 ##STR00615## 191 11.59 10 ##STR00616## 192
11.10 10 ##STR00617## 193 11.17 10 ##STR00618## 194 7.39 9
##STR00619## 195 9.15 9 ##STR00620## 196 9.30 2 ##STR00621## 197
9.41 2 ##STR00622## 198 9.40 2 ##STR00623## 199 10.53 2
##STR00624## 200 10.11 2 ##STR00625## 201 9.58 2 ##STR00626## 202
9.51 2 ##STR00627## 203 10.05 2 ##STR00628## 204 10.55 2
##STR00629## 205 10.36 2 ##STR00630## 206 9.36 2 ##STR00631## 207
9.41 2 ##STR00632## 208 9.49 2 ##STR00633## 209 9.85 2 ##STR00634##
210 9.69 2 ##STR00635## 211 9.81 2 ##STR00636## 212 10.13 2
##STR00637## 213 10.28 2 ##STR00638## 214 8.69 2 ##STR00639## 215
9.37 2 ##STR00640## 216 8.75 2 ##STR00641## 217 9.83 2 ##STR00642##
218 10.31 2 ##STR00643## 219 11.69 2 ##STR00644## 220 11.97 2
##STR00645## 221 9.89 2 ##STR00646## 222 10.27 2 ##STR00647## 223
10.46 2 ##STR00648## 224 10.82 2 ##STR00649## 225 11.81 2
##STR00650## 226 10.15 2 ##STR00651## 227 10.31 2 ##STR00652## 228
10.74 2 ##STR00653## 229 11.03 2 ##STR00654## 230 10.87 2
##STR00655## 231 10.29 2 ##STR00656## 232 7.95 2 ##STR00657## 233
8.64 2 ##STR00658## 234 8.34 2 ##STR00659## 235 8.94 2 ##STR00660##
236 9.02 2 ##STR00661## 237 10.95 2 ##STR00662## 238 11.19 2
##STR00663## 239 11.53 2 ##STR00664## 240 10.18 2 ##STR00665## 241
10.30 2 ##STR00666## 242 10.79 2 ##STR00667## 243 11.26 2
##STR00668## 244 10.10 2 ##STR00669## 245 10.58 2 ##STR00670## 246
11.33 2 ##STR00671## 247 11.19 2 ##STR00672## 248 11.03 2
##STR00673## 249 13.49 2
##STR00674## 250 14.78 2 ##STR00675## 251 16.51 2 ##STR00676## 252
19.99 2 ##STR00677## 253 10.79 2 ##STR00678## 254 7.29 2
##STR00679## 255 10.63 2 ##STR00680## 256 10.99 2 ##STR00681## 257
11.05 2 ##STR00682## 258 9.10 2 ##STR00683## 259 12.41 2
##STR00684## 260 12.85 2 ##STR00685## 261 9.20 10 ##STR00686## 262
10.23 10 ##STR00687## 263 7.31 9 ##STR00688## 264 9.29 9
##STR00689## 265 11.47 9 ##STR00690## 266 8.88 9 ##STR00691## 267
9.89 9 ##STR00692## 268 10.33 10 ##STR00693## 269 10.54 9
##STR00694## 270 10.37 9 ##STR00695## 271 10.92 9 ##STR00696## 272
11.07 9 ##STR00697## 273 10.13 9 ##STR00698## 274 10.61 9
##STR00699## 275 10.77 9 ##STR00700## 276 10.92 2 ##STR00701## 277
11.90 2 ##STR00702## 278 10.90 2 ##STR00703## 279 11.12 2
##STR00704## 280 10.30 2 ##STR00705## 281 12.30 2 ##STR00706## 282
10.91 2 ##STR00707## 283 11.00 2 ##STR00708## 284 11.58 2
##STR00709## 285 11.10 2 ##STR00710## 286 6.56 9 ##STR00711## 287
8.33 9 ##STR00712## 288 9.37 9 ##STR00713## 289 3.37 9 ##STR00714##
291 10.99 10 ##STR00715## 292 12.17 2 ##STR00716## 293 9.21 2
##STR00717## 294 11.59 2 ##STR00718## 295 12.56 2 ##STR00719## 296
11.25 10 ##STR00720## 297 10.43 10 ##STR00721## 298 10.36 10
##STR00722## 299 11.01 10 ##STR00723## 300 11.24 2 ##STR00724## 301
10.34 10 ##STR00725## 302 10.67 10 ##STR00726## 303 10.16 10
##STR00727## 304 10.74 10 ##STR00728## 305 11.39 2 ##STR00729## 306
11.20 2 ##STR00730## 307 11.35 2 ##STR00731## 308 11.61 2
##STR00732## 309 11.47 2 ##STR00733## 310 9.14 2 ##STR00734## 311
9.52 2 ##STR00735## 312 11.75 2 ##STR00736## 313 12.36 2
##STR00737## 314 9.14 2 ##STR00738## 315 11.45 2 ##STR00739## 316
9.55 2 ##STR00740## 317 11.18 2 ##STR00741## 318 11.26 2
##STR00742## 319 10.34 10 ##STR00743## 320 10.71 2 ##STR00744## 321
11.20 2 ##STR00745## 322 11.43 2 ##STR00746## 323 11.31 2
##STR00747## 324 11.38 2 ##STR00748## 325 9.87 2 ##STR00749## 326
11.34 2 ##STR00750## 327 13.32 10 ##STR00751## 328 10.59 10
##STR00752## 329 11.90 2 ##STR00753## 330 11.32 2 ##STR00754## 331
10.92 2 ##STR00755## 332 9.53 2 ##STR00756## 333 11.53 2
##STR00757## 334 10.61 10 ##STR00758## 335 10.87 10 ##STR00759##
336 10.26 10 ##STR00760## 337 10.30 2 ##STR00761## 338 10.36 2
##STR00762## 339 8.59 10 ##STR00763## 340 10.73 10 ##STR00764## 341
11.28 2 ##STR00765## 342 11.16 10 ##STR00766## 343 11.72 10
##STR00767## 344 11.13 10 ##STR00768## 345 10.83 10 ##STR00769##
346 11.03 10 ##STR00770## 347 11.60 10 ##STR00771## 348 11.38 10
##STR00772## 349 10.99 10 ##STR00773## 350 10.91 10 ##STR00774##
351 9.93 10 ##STR00775## 352 8.59 10 ##STR00776## 353 9.91 2
##STR00777## 354 10.23 2 ##STR00778## 355 10.17 2 ##STR00779## 356
8.40 2 ##STR00780## 357 10.72 2 ##STR00781## 358 10.95 2
##STR00782## 359 10.17 2 ##STR00783## 360 10.17 2 ##STR00784## 361
10.20 2 ##STR00785## 362 10.98 2 ##STR00786## 363 10.20 2
##STR00787## 364 10.67 2 ##STR00788## 365 9.14 2 ##STR00789## 366
8.65 2 ##STR00790## 367 10.78 2 ##STR00791## 368 10.84 2
##STR00792## 369 8.62 10 ##STR00793## 370 7.02 10 ##STR00794## 371
10.12 10 ##STR00795## 372 9.42 10 ##STR00796## 373 9.14 10
##STR00797## 374 10.78 10 ##STR00798## 375 10.82 10 ##STR00799##
376 10.61 10
##STR00800## 377 10.16 10 ##STR00801## 378 10.36 10 ##STR00802##
379 10.46 10 ##STR00803## 380 10.74 10 ##STR00804## 381 10.51 10
##STR00805## 382 11.40 10 ##STR00806## 383 12.06 2 ##STR00807## 384
9.29 2 ##STR00808## 385 9.43 2 ##STR00809## 386 12.10 2
##STR00810## 387 11.83 2 ##STR00811## 388 11.85 2 ##STR00812## 389
11.63 2 ##STR00813## 390 9.35 2 ##STR00814## 391 10.75 2
##STR00815## 392 10.33 2 ##STR00816## 393 9.56 2 ##STR00817## 394
9.96 2 ##STR00818## 395 9.49 12 ##STR00819## 396 9.61 12
##STR00820## 397 10.66 2 ##STR00821## 398 12.33 10 ##STR00822## 399
9.53 10 ##STR00823## 400 10.40 10 ##STR00824## 401 8.83 2
##STR00825## 402 8.19 2 ##STR00826## 403 8.26 2 ##STR00827## 404
8.66 2 ##STR00828## 405 7.85 2 ##STR00829## 406 10.47 10
##STR00830## 407 9.06 12 ##STR00831## 408 9.55 12 ##STR00832## 409
10.50 10 ##STR00833## 410 7.66 10 ##STR00834## 411 9.43 12
##STR00835## 412 8.90 12 ##STR00836## 413 8.95 13 ##STR00837## 414
9.14 13 ##STR00838## 415 9.12 13 ##STR00839## 416 8.93 13
##STR00840## 417 9.99 10 ##STR00841## 418 9.80 10 ##STR00842## 419
8.77 13 ##STR00843## 420 9.33 13 ##STR00844## 421 9.28 13
##STR00845## 422 9.46 13 ##STR00846## 423 9.72 13 ##STR00847## 424
8.77 13 ##STR00848## 425 8.92 13 ##STR00849## 426 8.39 13
##STR00850## 427 8.89 13 ##STR00851## 428 8.88 13 ##STR00852## 429
9.13 13 ##STR00853## 430 8.94 13 ##STR00854## 431 8.82 13
##STR00855## 432 9.66 13 ##STR00856## 433 10.22 10 ##STR00857## 434
8.09 13 ##STR00858## 435 9.44 13 ##STR00859## 436 10.40 10
##STR00860## 437 10.36 10 ##STR00861## 438 9.45 13 ##STR00862## 439
9.47 13 ##STR00863## 440 8.98 12 ##STR00864## 441 9.58 13
##STR00865## 442 9.72 13 ##STR00866## 443 8.23 14 ##STR00867## 444
9.97 14 ##STR00868## 445 10.21 14 ##STR00869## 446 10.23 14
##STR00870## 447 10.40 12 ##STR00871## 448 11.29 14 ##STR00872##
449 11.08 14 ##STR00873## 450 10.25 14 ##STR00874## 451 10.45 14
##STR00875## 452 8.21 10 ##STR00876## 453 11.44 10 ##STR00877## 454
11.13 10 ##STR00878## 455 10.97 10 ##STR00879## 456 9.29 14
##STR00880## 457 8.50 14 ##STR00881## 458 9.85 14 ##STR00882## 459
11.07 14 ##STR00883## 460 11.42 14 ##STR00884## 461 10.68 14
##STR00885## 462 11.49 14 ##STR00886## 463 10.52 14 ##STR00887##
464 10.81 14 ##STR00888## 465 8.26 10 ##STR00889## 466 7.58 10
##STR00890## 467 9.75 10 ##STR00891## 468 9.34 10 ##STR00892## 469
7.59 10 ##STR00893## 470 8.94 14 ##STR00894## 471 8.21 14
##STR00895## 472 10.33 14 ##STR00896## 473 9.43 14 ##STR00897## 474
10.61 14 ##STR00898## 475 10.27 14 ##STR00899## 476 10.22 14
##STR00900## 477 8.67 12 ##STR00901## 478 8.94 12 ##STR00902## 479
10.13 14 ##STR00903## 480 8.55 14 ##STR00904## 481 8.43 14
##STR00905## 482 9.52 14 ##STR00906## 483 8.75 14 ##STR00907## 484
10.15 14 ##STR00908## 485 10.38 14 ##STR00909## 486 9.85 14
##STR00910## 487 10.11 14 ##STR00911## 488 10.69 10 ##STR00912##
489 9.44 14 ##STR00913## 490 9.94 14 ##STR00914## 491 9.91 10
##STR00915## 492 7.56 10 ##STR00916## 493 10.05 10 ##STR00917## 494
9.97 10 ##STR00918## 495 10.68 10 ##STR00919## 496 10.92 10
##STR00920## 497 10.33 10 ##STR00921## 498 10.67 10 ##STR00922##
499 10.63 10 ##STR00923## 500 10.14 10 ##STR00924## 501 10.57
10
##STR00925## 502 10.23 14 ##STR00926## 503 10.20 14 ##STR00927##
504 10.78 14 ##STR00928## 505 10.40 14 ##STR00929## 506 10.24 14
##STR00930## 507 9.82 14 ##STR00931## 508 9.75 2 ##STR00932## 509
10.26 2 ##STR00933## 510 9.04 2 ##STR00934## 511 9.44 2
##STR00935## 512 9.80 2 ##STR00936## 513 9.95 2 ##STR00937## 514
10.10 2 ##STR00938## 515 8.50 2 ##STR00939## 516 8.57 2
##STR00940## 517 8.46 2 ##STR00941## 518 9.55 2 ##STR00942## 519
10.04 2 ##STR00943## 520 10.23 2 ##STR00944## 521 9.56 14
##STR00945## 522 8.78 14 ##STR00946## 523 9.25 14 ##STR00947## 524
10.065 14 ##STR00948## 525 10.02 14 ##STR00949## 526 10.28 14
##STR00950## 527 10.47 14 ##STR00951## 528 10.68 14 ##STR00952##
529 10.16 14 ##STR00953## 530 9.67 14 ##STR00954## 531 10.29 14
##STR00955## 532 10.36 14 ##STR00956## 533 10.39 14 ##STR00957##
534 9.75 14 ##STR00958## 535 10.94 14 ##STR00959## 536 10.69 10
##STR00960## 537 10.75 14 ##STR00961## 538 10.74 14 ##STR00962##
539 10.36 14 ##STR00963## 540 10.29 10 ##STR00964## 541 8.64 10
##STR00965## 542 9.35 10 ##STR00966## 543 10.84 10 ##STR00967## 544
10.34 10 ##STR00968## 545 10.40 10 ##STR00969## 546 10.21 10
##STR00970## 547 10.14 10 ##STR00971## 548 10.94 10 ##STR00972##
549 9.75 10 ##STR00973## 550 10.08 14 ##STR00974## 551 10.56 14
##STR00975## 552 10.15 14 ##STR00976## 553 10.01 14 ##STR00977##
554 9.91 14 ##STR00978## 555 10.44 14 ##STR00979## 556 10.94 14
##STR00980## 557 10.16 14 ##STR00981## 558 10.66 14 ##STR00982##
559 10.69 14 ##STR00983## 560 10.41 14 ##STR00984## 561 10.24 10
##STR00985## 562 10.98 10 ##STR00986## 563 10.71 10 ##STR00987##
564 10.62 10 ##STR00988## 565 10.50 10 ##STR00989## 566 10.13 10
##STR00990## 567 9.91 10 ##STR00991## 568 10.15 10 ##STR00992## 569
10.79 10 ##STR00993## 570 10.90 10 ##STR00994## 571 10.22 14
##STR00995## 572 10.35 14 ##STR00996## 573 10.05 10 ##STR00997##
574 11.47 10 ##STR00998## 575 10.02 10 ##STR00999## 576 9.09 10
##STR01000## 577 7.06 10 ##STR01001## 578 10.11 14 ##STR01002## 579
9.895 14 ##STR01003## 580 10.064 14 ##STR01004## 581 10.72 14
##STR01005## 582 10.23 14 ##STR01006## 583 10.89 14 ##STR01007##
584 9.60 10 ##STR01008## 585 10.03 10 ##STR01009## 586 9.93 10
##STR01010## 587 10.01 10 ##STR01011## 588 10.14 14 ##STR01012##
589 9.77 14 ##STR01013## 590 10.23 10 ##STR01014## 591 9.83 14
##STR01015## 592 10.41 10 ##STR01016## 593 7.80 10 ##STR01017## 594
10.38 9 ##STR01018## 595 10.34 9 ##STR01019## 596 10.27 9
##STR01020## 597 9.95 9 ##STR01021## 598 9.70 9 ##STR01022## 599
10.38 9 ##STR01023## 600 10.97 9 ##STR01024## 601 10.36 10
##STR01025## 602 10.72 2 ##STR01026## 603 10.52 2 ##STR01027## 604
10.532 2 ##STR01028## 605 10.91 2 ##STR01029## 606 9.93 2
##STR01030## 607 10.61 2 ##STR01031## 608 10.20 2 ##STR01032## 609
10.16 10 ##STR01033## 610 10.65 10 ##STR01034## 611 10.15 10
##STR01035## 612 9.91 10 ##STR01036## 613 10.39 10 ##STR01037## 614
9.25 10 ##STR01038## 615 10.53 10 ##STR01039## 616 8.55 10
##STR01040## 617 10.27 10 ##STR01041## 618 10.6 10 ##STR01042## 619
10.97 10 ##STR01043## 620 10.10 10 ##STR01044## 621 10.70 10
##STR01045## 622 7.70 10 ##STR01046## 623 10.35 10 ##STR01047## 624
10.56 10 ##STR01048## 625 10.29 10 ##STR01049## 626 9.39 10
##STR01050## 627 10.30 10
##STR01051## 628 9.20 10 ##STR01052## 629 10.90 10 ##STR01053## 630
9.66 14 ##STR01054## 631 10.32 14 ##STR01055## 632 10.10 14
##STR01056## 633 9.80 10 ##STR01057## 634 10.62 10 ##STR01058## 635
10.17 10 ##STR01059## 636 10.25 10 ##STR01060## 637 10.50 14
##STR01061## 638 10.94 14 ##STR01062## 639 9.88 10 ##STR01063## 640
10.38 10 ##STR01064## 641 10.45 10 ##STR01065## 642 10.523 10
##STR01066## 644 10.20 14 ##STR01067## 645 9.68 14 ##STR01068## 646
9.80 14 ##STR01069## 647 10.50 14 ##STR01070## 648 10.50 14
##STR01071## 649 8.51 14 ##STR01072## 650 9.62 14 ##STR01073## 651
10.65 10 ##STR01074## 652 9.91 14 ##STR01075## 653 10.81 14
##STR01076## 654 10.10 14 ##STR01077## 655 9.87 14 ##STR01078## 656
10.47 14 ##STR01079## 657 10.47 14 ##STR01080## 658 10.43 14
##STR01081## 659 9.57 14 ##STR01082## 660 10.23 2 ##STR01083## 661
10.29 14 ##STR01084## 662 10.16 14 ##STR01085## 663 9.79 14
##STR01086## 664 9.59 14 ##STR01087## 665 10.68 10 ##STR01088## 666
10.68 10 ##STR01089## 667 10.63 10 ##STR01090## 668 10.38 10
##STR01091## 669 10.33 10 ##STR01092## 670 9.57 14 ##STR01093## 671
9.38 14 ##STR01094## 672 9.67 14 ##STR01095## 673 9.40 14
##STR01096## 674 8.92 14 ##STR01097## 675 8.94 14 ##STR01098## 676
10.34 14 ##STR01099## 677 9.79 14 ##STR01100## 678 10.92 14
##STR01101## 679 10.45 14 ##STR01102## 680 9.91 14 ##STR01103## 681
10.24 14 ##STR01104## 682 8.26 14 ##STR01105## 683 12.00 14
##STR01106## 684 11.47 14 ##STR01107## 685 9.34 14 ##STR01108## 686
9.88 14 ##STR01109## 687 9.29 14 ##STR01110## 688 9.37 14
##STR01111## 689 9.25 14 ##STR01112## 690 8.90 14 ##STR01113## 691
8.03 14 ##STR01114## 692 9.09 14 ##STR01115## 693 9.26 14
##STR01116## 694 8.22 14 ##STR01117## 695 7.82 14 ##STR01118## 696
8.82 14 ##STR01119## 697 10.53 14 ##STR01120## 698 10.49 14
##STR01121## 699 9.30 14 ##STR01122## 700 9.14 14 ##STR01123## 701
10.30 14 ##STR01124## 702 10.21 14 ##STR01125## 703 10.04 14
##STR01126## 704 13.49 14 ##STR01127## 705 10.85 14 ##STR01128##
706 10.85 2 ##STR01129## 707 10.60 2 ##STR01130## 708 8.40 2
##STR01131## 709 8.91 2 ##STR01132## 710 9.442 2 ##STR01133## 711
9.937 2 ##STR01134## 712 10.943 2 ##STR01135## 713 10.11 14
##STR01136## 714 9.15 14 ##STR01137## 715 10.02 14 ##STR01138## 716
10.09 14 ##STR01139## 717 8.80 14 ##STR01140## 718 9.35 14
##STR01141## 719 9.83 14 ##STR01142## 720 8.85 14 ##STR01143## 721
7.33 12 ##STR01144## 722 7.88 14 ##STR01145## 723 10.36 14
##STR01146## 724 10.28 14 ##STR01147## 725 8.32 14 ##STR01148## 726
8.84 14 ##STR01149## 727 8.63 14 ##STR01150## 728 7.72 14
##STR01151## 729 8.79 14 ##STR01152## 730 6.91 14 ##STR01153## 731
7.30 14 ##STR01154## 732 7.83 14 ##STR01155## 733 8.31 14
##STR01156## 734 8.83 14 ##STR01157## 735 9.33 14 ##STR01158## 736
10.33 14 ##STR01159## 737 10.23 14 ##STR01160## 738 8.32 14
##STR01161## 739 8.83 14 ##STR01162## 740 8.35 14 ##STR01163## 741
8.41 14 ##STR01164## 742 7.67 14 ##STR01165## 743 7.93 14
##STR01166## 744 7.99 14 ##STR01167## 745 9.45 14 ##STR01168## 746
7.88 14 ##STR01169## 747 8.71 14 ##STR01170## 748 9.64 14
##STR01171## 749 8.10 14 ##STR01172## 750 8.47 14 ##STR01173## 751
8.71 14 ##STR01174## 752 9.33 14 ##STR01175## 753 8.33 14
##STR01176## 754 9.34 14 ##STR01177## 755 9.81 14 ##STR01178## 756
9.40 14 ##STR01179## 757 9.78 14 ##STR01180## 758 9.24 14
##STR01181## 759 10.11 14 ##STR01182## 760 10.10 14 ##STR01183##
761 8.18 14 ##STR01184## 762 9.33 14 ##STR01185## 763 9.73 14
##STR01186## 764 10.78 14 ##STR01187## 765 10.71 14 ##STR01188##
766 8.78 14 ##STR01189## 767 9.24 14 ##STR01190## 768 8.83 14
##STR01191## 769 8.67 14 ##STR01192## 770 9.773 14 ##STR01193## 771
9.32 14 ##STR01194## 772 10.26 14 ##STR01195## 773 9.72 14
##STR01196## 774 10.19 10 ##STR01197## 775 8.883 14 ##STR01198##
776 10.03 14 ##STR01199## 777 9.19 14 ##STR01200## 778 10.31 14
##STR01201## 779 8.12 14 ##STR01202## 780 7.43 14 ##STR01203## 781
7.63 14 ##STR01204## 782 7.59 14 ##STR01205## 783 8.39 14
##STR01206## 784 6.75 14 ##STR01207## 785 7.65 14 ##STR01208## 786
8.14 14 ##STR01209## 787 8.43 14 ##STR01210## 788 7.43 14
##STR01211## 789 8.19 14 ##STR01212## 790 10.67 10 ##STR01213## 791
10.89 10 ##STR01214## 792 10.02 14 ##STR01215## 793 9.72 14
##STR01216## 794 10.30 14 ##STR01217## 795 9.38 14 ##STR01218## 796
8.90 14 ##STR01219## 797 8.69 14 ##STR01220## 798 9.05 14
##STR01221## 799 8.58 14 ##STR01222## 800 6.898 14 ##STR01223## 801
10.18 14 ##STR01224## 802 9.38 14 ##STR01225## 803 10.70 2
##STR01226## 804 9.66 14 ##STR01227## 806 9.74 14 ##STR01228## 807
9.91 14 ##STR01229## 808 9.71 14 ##STR01230## 809 9.49 14
##STR01231## 810 9.78 14 ##STR01232## 811 10.03 10 ##STR01233## 812
9.00 10 ##STR01234## 813 10.13 14 ##STR01235## 814 10.18 14
##STR01236## 815 9.72 14 ##STR01237## 816 8.59 14 ##STR01238## 817
8.97 14 ##STR01239## 818 9.30 14 ##STR01240## 819 10.35 14
##STR01241## 820 9.56 14 ##STR01242## 821 9.78 14 ##STR01243## 822
9.70 14 ##STR01244## 823 10.30 14 ##STR01245## 824 10.14 14
##STR01246## 825 10.23 14 ##STR01247## 826 8.21 14 ##STR01248## 827
9.72 14 ##STR01249## 828 10.35 14 ##STR01250## 829 9.84 14
##STR01251## 830 9.66 14 ##STR01252## 832 9.20 14 ##STR01253## 833
10.33 14 ##STR01254## 834 10.19 14 ##STR01255## 835 9.04 14
##STR01256## 836 10.15 14 ##STR01257## 837 10.02 14 ##STR01258##
838 8.69 14 ##STR01259## 839 8.91 14 ##STR01260## 840 9.35 14
##STR01261## 841 9.31 14 ##STR01262## 842 9.01 14 ##STR01263## 843
9.79 14 ##STR01264## 844 10.21 14 ##STR01265## 845 10.11 14
##STR01266## 846 9.38 14 ##STR01267## 847 10.77 14 ##STR01268## 848
9.76 14 ##STR01269## 849 10.06 14 ##STR01270## 850 10.93 14
##STR01271## 851 10.85 14 ##STR01272## 852 10.92 14 ##STR01273##
853 10.47 14 ##STR01274## 855 9.34 14 ##STR01275## 856 9.18 14
##STR01276## 857 9.33 14 ##STR01277## 858 10.34 14 ##STR01278## 859
10.32 14 ##STR01279## 860 9.02 14 ##STR01280## 861 8.85 14
##STR01281## 862 10.34 14 ##STR01282## 863 9.24 14 ##STR01283## 864
9.61 14 ##STR01284## 865 9.25 14 ##STR01285## 866 10.07 14
##STR01286## 867 8.61 14 ##STR01287## 868 10.08 14 ##STR01288## 869
10.11 2 ##STR01289## 870 9.84 2 ##STR01290## 871 9.78 14
##STR01291## 872 10.13 14 ##STR01292## 873 9.45 14 ##STR01293## 874
9.48 14 ##STR01294## 875 10.46 14 ##STR01295## 876 10.13 14
##STR01296## 877 10.59 14 ##STR01297## 878 9.55 14 ##STR01298## 879
12.75 14 ##STR01299## 880 10.25 14 ##STR01300## 881 10.23 14
##STR01301## 882 10.19 14
##STR01302## 883 10.50 14 ##STR01303## 884 10.09 14 ##STR01304##
885 9.79 14 ##STR01305## 886 9.91 14 ##STR01306## 887 10.38 14
##STR01307## 888 10.29 14 ##STR01308## 889 10.13 14 ##STR01309##
890 10.30 14 ##STR01310## 891 10.13 14 ##STR01311## 892 10.33 14
##STR01312## 893 10.38 14 ##STR01313## 894 10.49 14 ##STR01314##
895 10.28 11 ##STR01315## 896 11.10 11 ##STR01316## 897 11.09 11
##STR01317## 898 11.19 11 ##STR01318## 899 11.16 11 ##STR01319##
900 10.75 11 ##STR01320## 901 10.90 11 ##STR01321## 902 10.96 11
##STR01322## 903 10.02 11 ##STR01323## 904 9.62 11 ##STR01324## 905
11.30 11 ##STR01325## 906 7.72 11 ##STR01326## 907 8.30 11
##STR01327## 908 10.21 11 ##STR01328## 909 11.18 11 ##STR01329##
910 11.33 11 ##STR01330## 911 9.90 11 ##STR01331## 912 10.08 11
##STR01332## 913 9.80 11 ##STR01333## 914 11.02 11 ##STR01334## 915
9.51 11 ##STR01335## 916 10.14 11 ##STR01336## 917 9.70 11
##STR01337## 918 10.68 11 ##STR01338## 919 8.49 14 ##STR01339## 920
9.31 14 ##STR01340## 921 8.63 14 ##STR01341## 922 8.80 14
##STR01342## 923 9.75 14 ##STR01343## 924 9.52 14 ##STR01344## 925
8.86 14 ##STR01345## 926 10.49 14 ##STR01346## 927 8.11 14
##STR01347## 928 7.81 14 ##STR01348## 929 8.77 14 ##STR01349## 930
7.80 14 ##STR01350## 931 8.06 14 ##STR01351## 932 8.89 14
##STR01352## 933 8.81 14 ##STR01353## 934 8.60 14 ##STR01354## 935
8.98 14 ##STR01355## 936 9.90 14 ##STR01356## 937 10.05 14
##STR01357## 938 9.26 14 ##STR01358## 939 9.98 14 ##STR01359## 940
9.32 14 ##STR01360## 941 9.61 14 ##STR01361## 942 9.07 14
##STR01362## 943 9.42 14 ##STR01363## 944 9.47 14 ##STR01364## 945
9.773 14 ##STR01365## 946 8.61 11 ##STR01366## 947 9.77 14
##STR01367## 948 10.12 14 ##STR01368## 949 9.55 14 ##STR01369## 950
9.83 14 ##STR01370## 951 10.15 14 ##STR01371## 952 10.52 14
##STR01372## 953 9.75 14 ##STR01373## 954 9.12 14 ##STR01374## 955
9.67 14 ##STR01375## 956 9.61 14 ##STR01376## 957 9.69 14
##STR01377## 958 10.01 14 ##STR01378## 959 10.06 14 ##STR01379##
960 8.61 14 ##STR01380## 961 2.38 27 ##STR01381## 962 2.61 27
##STR01382## 963 2.64 27 ##STR01383## 964 2.91 27 ##STR01384## 965
3.11 27 ##STR01385## 966 2.66 27 ##STR01386## 967 2.96 27
##STR01387## 968 2.88 27 ##STR01388## 969 2.36 27 ##STR01389## 970
2.76 27 ##STR01390## 971 2.31 27 ##STR01391## 972 2.30 27
##STR01392## 973 2.02 27 ##STR01393## 974 2.42 27 ##STR01394## 975
2.38 24 ##STR01395## 976 2.38 17 ##STR01396## 977 2.38 22
##STR01397## 978 3.25 27 ##STR01398## 979 2.28 23 ##STR01399## 980
2.04 23 ##STR01400## 981 2.23 23 ##STR01401## 982 2.24 23
##STR01402## 983 1.74 24 ##STR01403## 984 2.38 23 ##STR01404## 985
2.38 24 ##STR01405## 986 2.38 23 ##STR01406## 987 2.38 23
##STR01407## 988 2.38 23 ##STR01408## 989 2.12 27 ##STR01409## 990
2.95 24 ##STR01410## 991 2.00 27 ##STR01411## 992 2.41 17
##STR01412## 993 2.19 17 ##STR01413## 994 2.13 17 ##STR01414## 995
2.06 17 ##STR01415## 996 1.88 17 ##STR01416## 997 2.01 17
##STR01417## 998 2.18 17 ##STR01418## 999 2.26 17 ##STR01419## 1000
2.13 17 ##STR01420## 1001 2.38 17 ##STR01421## 1002 1.98 17
##STR01422## 1003 2.03 17 ##STR01423## 1004 2.01 17 ##STR01424##
1005 1.83 17 ##STR01425## 1006 1.96 17 ##STR01426## 1007 2.31
17
##STR01427## 1008 2.38 21 ##STR01428## 1009 2.38 23 ##STR01429##
1010 2.38 23 ##STR01430## 1011 2.38 17 ##STR01431## 1012 2.08 17
##STR01432## 1013 2.22 17 ##STR01433## 1014 2.50 17 ##STR01434##
1015 2.45 17 ##STR01435## 1016 2.57 17 ##STR01436## 1017 2.93 17
##STR01437## 1018 2.35 17 ##STR01438## 1019 2.46 17 ##STR01439##
1020 2.35 17 ##STR01440## 1021 2.88 17 ##STR01441## 1022 2.67 17
##STR01442## 1023 2.83 17 ##STR01443## 1024 2.70 17 ##STR01444##
1025 2.65 17 ##STR01445## 1026 2.60 23 ##STR01446## 1027 2.87 24
##STR01447## 1028 2.40 24 ##STR01448## 1029 2.53 23 ##STR01449##
1030 2.40 23 ##STR01450## 1031 2.68 23 ##STR01451## 1032 2.43 17
##STR01452## 1033 2.73 17 ##STR01453## 1034 2.72 17 ##STR01454##
1035 2.73 17 ##STR01455## 1036 2.75 23 ##STR01456## 1037 2.80 23
##STR01457## 1038 2.90 17 ##STR01458## 1039 3.18 17 ##STR01459##
1040 2.63 17 ##STR01460## 1041 2.73 17 ##STR01461## 1042 2.67 17
##STR01462## 1043 2.47 17 ##STR01463## 1044 2.80 17 ##STR01464##
1045 2.75 17 ##STR01465## 1046 2.98 17 ##STR01466## 1047 2.01 24
##STR01467## 1048 2.38 17 ##STR01468## 1049 1.80 27 ##STR01469##
1050 1.71 17 ##STR01470## 1051 2.38 23 ##STR01471## 1052 2.90 17
##STR01472## 1053 2.70 17 ##STR01473## 1054 3.43 17 ##STR01474##
1055 2.78 17 ##STR01475## 1056 10.82 10 ##STR01476## 1057 10.71 10
##STR01477## 1058 11.32 10 ##STR01478## 1059 10.72 10 ##STR01479##
1060 9.87 10 ##STR01480## 1061 9.54 14 ##STR01481## 1062 9.11 14
##STR01482## 1063 9.06 14 ##STR01483## 1064 9.25 14 ##STR01484##
1065 9.32 14 ##STR01485## 1066 8.90 14 ##STR01486## 1067 10.69 10
##STR01487## 1068 8.54 14 ##STR01488## 1069 9.77 14 ##STR01489##
1070 9.87 14 ##STR01490## 1071 9.67 14 ##STR01491## 1072 9.07 14
##STR01492## 1073 9.58 14 ##STR01493## 1074 9.43 14 ##STR01494##
1075 9.98 14 ##STR01495## 1076 9.88 14 ##STR01496## 1077 9.23 14
##STR01497## 1078 9.11 14 ##STR01498## 1079 8.70 14 ##STR01499##
1080 9.83 14 ##STR01500## 1081 10.16 14 ##STR01501## 1082 10.12 14
##STR01502## 1083 9.58 14 ##STR01503## 1084 9.38 14 ##STR01504##
1085 8.41 14 ##STR01505## 1086 8.67 14 ##STR01506## 1087 8.67 14
##STR01507## 1088 9.58 14 ##STR01508## 1089 8.36 14 ##STR01509##
1090 7.66 14 ##STR01510## 1091 7.42 14 ##STR01511## 1092 7.86 14
##STR01512## 1093 7.78 14 ##STR01513## 1094 9.13 14 ##STR01514##
1095 10.34 14 ##STR01515## 1096 8.57 14 ##STR01516## 1097 10.00 14
##STR01517## 1098 9.80 14 ##STR01518## 1099 8.30 14 ##STR01519##
1100 10.07 14 ##STR01520## 1101 9.61 14 ##STR01521## 1102 9.32 14
##STR01522## 1103 8.57 14 ##STR01523## 1104 8.01 14 ##STR01524##
1105 8.86 14 ##STR01525## 1106 8.78 14 ##STR01526## 1107 9.10 14
##STR01527## 1108 8.70 14 ##STR01528## 1109 8.24 14 ##STR01529##
1110 8.65 14 ##STR01530## 1111 8.80 14 ##STR01531## 1112 9.14 14
##STR01532## 1113 9.13 14 ##STR01533## 1114 8.54 14 ##STR01534##
1115 9.51 14 ##STR01535## 1116 9.46 14 ##STR01536## 1117 8.64 14
##STR01537## 1118 8.55 14 ##STR01538## 1119 9.38 14 ##STR01539##
1120 9.74 14 ##STR01540## 1121 9.68 14 ##STR01541## 1122 9.39 14
##STR01542## 1123 8.65 14 ##STR01543## 1124 8.00 14 ##STR01544##
1125 8.25 14 ##STR01545## 1126 8.00 14 ##STR01546## 1127 8.02 14
##STR01547## 1128 11.07 10 ##STR01548## 1129 8.10 14 ##STR01549##
1130 7.35 14 ##STR01550## 1131 8.10 14 ##STR01551## 1132 7.40 14
##STR01552## 1133 8.01 14
##STR01553## 1134 7.90 14 ##STR01554## 1135 9.75 14 ##STR01555##
1136 9.22 14 ##STR01556## 1137 10.70 10 ##STR01557## 1138 8.69 14
##STR01558## 1139 8.32 14 ##STR01559## 1140 8.56 14 ##STR01560##
1141 8.42 14 ##STR01561## 1142 7.99 14 ##STR01562## 1143 10.48 14
##STR01563## 1144 10.74 14 ##STR01564## 1145 9.61 14 ##STR01565##
1146 8.88 14 ##STR01566## 1147 8.73 14 ##STR01567## 1148 8.47 14
##STR01568## 1149 8.28 14 ##STR01569## 1150 9.82 14 ##STR01570##
1151 7.86 14 ##STR01571## 1152 10.43 14 ##STR01572## 1153 9.63 14
##STR01573## 1154 9.37 14 ##STR01574## 1155 10.30 14 ##STR01575##
1156 9.93 14 ##STR01576## 1157 10.53 14 ##STR01577## 1158 9.09 14
##STR01578## 1159 9.90 14 ##STR01579## 1160 9.55 14 ##STR01580##
1161 10.04 14 ##STR01581## 1162 8.74 14 ##STR01582## 1163 9.39 14
##STR01583## 1164 9.38 14 ##STR01584## 1165 8.70 14 ##STR01585##
1166 9.23 14 ##STR01586## 1167 9.692 14 ##STR01587## 1168 9.423 14
##STR01588## 1169 9.782 14 ##STR01589## 1170 10.137 14 ##STR01590##
1171 9.08 14 ##STR01591## 1172 8.78 14 ##STR01592## 1173 9.19 14
##STR01593## 1174 8.94 14 ##STR01594## 1175 9.55 14 ##STR01595##
1176 9.46 14 ##STR01596## 1177 9.56 14 ##STR01597## 1178 10.23 14
##STR01598## 1179 10.44 14 ##STR01599## 1180 6.81 14 ##STR01600##
1181 10.46 14 ##STR01601## 1182 10.70 14 ##STR01602## 1183 7.97 14
##STR01603## 1184 8.64 14 ##STR01604## 1185 8.91 14 ##STR01605##
1186 7.47 14 ##STR01606## 1187 9.119 14 ##STR01607## 1188 8.80 14
##STR01608## 1189 8.89 14 ##STR01609## 1190 8.60 14 ##STR01610##
1191 8.86 14 ##STR01611## 1192 8.57 14 ##STR01612## 1193 7.65 14
##STR01613## 1194 8.08 14 ##STR01614## 1195 8.38 14 ##STR01615##
1196 9.09 14 ##STR01616## 1197 7.38 14 ##STR01617## 1198 9.19 14
##STR01618## 1199 9.39 14 ##STR01619## 1200 9.15 14 ##STR01620##
1201 7.74 14 ##STR01621## 1202 7.80 14 ##STR01622## 1203 9.01 14
##STR01623## 1204 8.65 14 ##STR01624## 1205 9.01 14 ##STR01625##
1206 8.62 14 ##STR01626## 1207 8.39 14 ##STR01627## 1208 9.08 14
##STR01628## 1209 8.66 14 ##STR01629## 1210 9.32 14 ##STR01630##
1211 9.68 14 ##STR01631## 1212 9.97 14 ##STR01632## 1213 8.00 14
##STR01633## 1214 9.59 14 ##STR01634## 1215 8.48 14 ##STR01635##
1216 8.53 14 ##STR01636## 1217 8.53 14 ##STR01637## 1218 8.536 14
##STR01638## 1219 9.282 14 ##STR01639## 1220 9.33 14 ##STR01640##
1221 9.83 14 ##STR01641## 1222 8.70 14 ##STR01642## 1223 8.26 14
##STR01643## 1224 8.44 14 ##STR01644## 1225 8.76 14 ##STR01645##
1226 9.88 14 ##STR01646## 1227 9.32 10 ##STR01647## 1228 9.00 10
##STR01648## 1229 8.31 10 ##STR01649## 1230 8.70 10 ##STR01650##
1231 8.59 10 ##STR01651## 1232 9.41 10 ##STR01652## 1233 8.99 10
##STR01653## 1234 9.65 10 ##STR01654## 1235 9.17 10 ##STR01655##
1236 9.76 10 ##STR01656## 1237 9.95 10 ##STR01657## 1238 9.98 10
##STR01658## 1239 10.00 10 ##STR01659## 1240 9.30 10 ##STR01660##
1241 8.90 10 ##STR01661## 1242 8.55 10 ##STR01662## 1243 9.38 10
##STR01663## 1244 8.93 10 ##STR01664## 1245 8.98 10 ##STR01665##
1246 7.95 10 ##STR01666## 1247 8.90 10 ##STR01667## 1248 7.95 10
##STR01668## 1249 7.90 10 ##STR01669## 1250 8.46 10 ##STR01670##
1251 8.53 10 ##STR01671## 1252 8.56 10 ##STR01672## 1253 9.73 10
##STR01673## 1254 8.34 10 ##STR01674## 1255 8.10 10 ##STR01675##
1256 8.15 10 ##STR01676## 1257 7.58 10 ##STR01677## 1258 8.28
10
##STR01678## 1259 7.85 10 ##STR01679## 1260 8.49 10 ##STR01680##
1261 9.30 10 ##STR01681## 1262 9.77 10 ##STR01682## 1263 7.81 10
##STR01683## 1264 8.32 10 ##STR01684## 1265 11.31 10 ##STR01685##
1266 9.08 10 ##STR01686## 1267 7.68 10 ##STR01687## 1268 8.50 10
##STR01688## 1269 10.74 10 ##STR01689## 1270 10.81 10 ##STR01690##
1271 10.09 10 ##STR01691## 1272 8.08 10 ##STR01692## 1273 8.55 10
##STR01693## 1274 8.46 10 ##STR01694## 1275 8.31 10 ##STR01695##
1276 9.12 10 ##STR01696## 1277 8.69 10 ##STR01697## 1278 8.92 10
##STR01698## 1279 10.63 10 ##STR01699## 1280 9.57 14 ##STR01700##
1281 10.40 14 ##STR01701## 1282 9.03 14 ##STR01702## 1283 8.48 14
##STR01703## 1284 7.97 14 ##STR01704## 1285 8.46 14 ##STR01705##
1286 8.68 14 ##STR01706## 1287 8.02 14 ##STR01707## 1288 8.56 14
##STR01708## 1289 7.76 14 ##STR01709## 1290 7.33 14 ##STR01710##
1291 7.35 14 ##STR01711## 1292 7.01 14 ##STR01712## 1293 8.63 14
##STR01713## 1294 9.53 14 ##STR01714## 1295 8.50 14 ##STR01715##
1296 9.50 14 ##STR01716## 1297 6.15 14 ##STR01717## 1298 9.51 14
##STR01718## 1299 8.10 14 ##STR01719## 1300 7.63 14 ##STR01720##
1301 7.51 14 ##STR01721## 1302 8.55 14 ##STR01722## 1303 6.85 14
##STR01723## 1304 8.41 14 ##STR01724## 1305 7.81 14 ##STR01725##
1306 7.49 14 ##STR01726## 1307 6.29 14 ##STR01727## 1308 9.96 14
##STR01728## 1309 9.58 14 ##STR01729## 1310 11.36 14 ##STR01730##
1311 7.04 14 ##STR01731## 1312 9.45 14 ##STR01732## 1313 8.62 14
##STR01733## 1314 8.47 14 ##STR01734## 1315 8.34 14 ##STR01735##
1316 9.77 14 ##STR01736## 1317 11.20 14 ##STR01737## 1318 7.98 14
##STR01738## 1319 8.299 14 ##STR01739## 1320 9.231 14 ##STR01740##
1321 10.47 14 ##STR01741## 1322 9.86 14 ##STR01742## 1323 10.05 14
##STR01743## 1324 10.43 14 ##STR01744## 1325 9.72 14 ##STR01745##
1326 9.79 14 ##STR01746## 1327 9.96 14 ##STR01747## 1328 10.42 14
##STR01748## 1329 7.82 14 ##STR01749## 1330 8.35 14 ##STR01750##
1331 8.80 14 ##STR01751## 1332 9.25 14 ##STR01752## 1333 10.90 10
##STR01753## 1334 10.25 10 ##STR01754## 1335 10.8 10 ##STR01755##
1336 10.94 10 ##STR01756## 1337 10.25 10 ##STR01757## 1338 7.49 10
##STR01758## 1339 9.69 10 ##STR01759## 1340 9.51 10 ##STR01760##
1341 10.10 10 ##STR01761## 1342 9.74 14 ##STR01762## 1343 11.07 10
##STR01763## 1344 10.422 14 ##STR01764## 1345 8.83 14 ##STR01765##
1346 10.38 14 ##STR01766## 1347 8.23 14 ##STR01767## 1348 9.47 14
##STR01768## 1349 5.88 14 ##STR01769## 1350 7.58 14 ##STR01770##
1351 8.15 14 ##STR01771## 1352 7.65 14 ##STR01772## 1353 5.83 14
##STR01773## 1354 7.71 20 ##STR01774## 1355 9.73 10 ##STR01775##
1356 9.86 10 ##STR01776## 1357 8.94 20 ##STR01777## 1358 8.92 20
##STR01778## 1359 10.00 14 ##STR01779## 1360 9.58 14 ##STR01780##
1361 10.29 14 ##STR01781## 1362 9.26 20 ##STR01782## 1363 9.32 20
##STR01783## 1364 9.28 14 ##STR01784## 1365 9.28 14 ##STR01785##
1366 9.163 20 ##STR01786## 1367 8.14 20 ##STR01787## 1368 8.16 20
##STR01788## 1369 8.51 20 ##STR01789## 1370 8.25 20 ##STR01790##
1371 7.92 20 ##STR01791## 1372 8.63 20 ##STR01792## 1373 7.97 20
##STR01793## 1374 8.47 20 ##STR01794## 1375 9.17 20 ##STR01795##
1376 7.52 20 ##STR01796## 1377 8.47 20 ##STR01797## 1378 7.55 20
##STR01798## 1379 7.23 20 ##STR01799## 1380 7.88 20 ##STR01800##
1381 8.98 20 ##STR01801## 1382 8.32 20 ##STR01802## 1383 9.05 20
##STR01803## 1384 8.60 20
##STR01804## 1385 7.81 20 ##STR01805## 1386 8.16 20 ##STR01806##
1387 8.65 20 ##STR01807## 1388 8.09 20 ##STR01808## 1389 8.65 20
##STR01809## 1390 8.12 20 ##STR01810## 1391 7.47 28 ##STR01811##
1392 11.41 10 ##STR01812## 1393 8.17 28 ##STR01813## 1394 9.90 14
##STR01814## 1395 9.20 14 ##STR01815## 1396 8.85 14 ##STR01816##
1397 8.44 20 ##STR01817## 1398 8.54 20 ##STR01818## 1399 8.333 28
##STR01819## 1400 7.60 28 ##STR01820## 1401 8.60 28 ##STR01821##
1402 9.66 28 ##STR01822## 1403 9.37 28 ##STR01823## 1404 8.15 28
##STR01824## 1405 8.30 28 ##STR01825## 1406 7.69 28 ##STR01826##
1407 8.43 28 ##STR01827## 1408 8.08 28 ##STR01828## 1409 8.06 28
##STR01829## 1410 7.81 28 ##STR01830## 1411 5.39 10 ##STR01831##
1412 9.22 10 ##STR01832## 1413 10.45 10 ##STR01833## 1414 10.53 10
##STR01834## 1415 8.43 10 ##STR01835## 1416 8.19 10 ##STR01836##
1417 7.15 20 ##STR01837## 1418 6.65 20 ##STR01838## 1419 10.82 10
##STR01839## 1420 5.27 10 ##STR01840## 1421 8.49 10 ##STR01841##
1422 8.29 10 ##STR01842## 1423 7.24 10 ##STR01843## 1424 10.32 10
##STR01844## 1425 7.80 10 ##STR01845## 1426 7.99 10 ##STR01846##
1427 9.95 10 ##STR01847## 1428 9.648 10 ##STR01848## 1429 10.41 10
##STR01849## 1430 8.43 10 ##STR01850## 1431 9.55 10 ##STR01851##
1432 8.79 10 ##STR01852## 1433 10.35 10 ##STR01853## 1434 5.12 10
##STR01854## 1435 7.12 10 ##STR01855## 1436 6.95 10 ##STR01856##
1437 10.60 10 ##STR01857## 1438 10.83 10 ##STR01858## 1439 11.84 10
##STR01859## 1440 9.31 10 ##STR01860## 1441 10.79 28 ##STR01861##
1442 8.52 28 ##STR01862## 1443 8.92 28 ##STR01863## 1444 8.48 28
##STR01864## 1445 7.28 28 ##STR01865## 1446 8.63 28 ##STR01866##
1447 9.19 28 ##STR01867## 1448 8.90 28 ##STR01868## 1449 8.68 28
##STR01869## 1450 8.33 28 ##STR01870## 1451 8.36 28 ##STR01871##
1452 8.32 28 ##STR01872## 1453 8.70 28 ##STR01873## 1454 8.76 28
##STR01874## 1455 8.95 28 ##STR01875## 1456 9.15 28 ##STR01876##
1457 9.19 28 ##STR01877## 1458 8.55 28 ##STR01878## 1459 8.35 28
##STR01879## 1460 7.13 28 ##STR01880## 1461 8.40 28 ##STR01881##
1462 9.15 28 ##STR01882## 1463 7.35 28 ##STR01883## 1464 9.16 28
##STR01884## 1465 8.74 28 ##STR01885## 1466 8.66 28 ##STR01886##
1467 7.93 28 ##STR01887## 1468 8.61 28 ##STR01888## 1469 9.55 28
##STR01889## 1470 9.32 28 ##STR01890## 1471 7.87 28 ##STR01891##
1472 9.08 28 ##STR01892## 1473 8.87 28 ##STR01893## 1474 7.12 28
##STR01894## 1475 6.69 28 ##STR01895## 1476 6.80 28 ##STR01896##
1477 6.04 28 ##STR01897## 1478 6.67 28 ##STR01898## 1479 6.44 28
##STR01899## 1480 6.46 28 ##STR01900## 1481 6.71 28 ##STR01901##
1482 6.61 28 ##STR01902## 1483 5.10 28 ##STR01903## 1484 5.46 28
##STR01904## 1485 4.87 28 ##STR01905## 1486 5.89 28 ##STR01906##
1487 5.58 28 ##STR01907## 1488 6.23 28 ##STR01908## 1489 4.99 28
##STR01909## 1490 6.68 28 ##STR01910## 1491 5.62 28 ##STR01911##
1492 6.25 28 ##STR01912## 1493 7.73 28 ##STR01913## 1494 8.28 10
##STR01914## 1495 7.44 10 ##STR01915## 1496 9.22 10 ##STR01916##
1497 7.49 10 ##STR01917## 1498 4.39 10 ##STR01918## 1499 6.67 10
##STR01919## 1500 6.80 10 ##STR01920## 1501 5.68 10 ##STR01921##
1502 8.32 10 ##STR01922## 1503 8.76 10 ##STR01923## 1504 8.59 10
##STR01924## 1505 9.00 10 ##STR01925## 1506 7.43 10 ##STR01926##
1507 8.93 10 ##STR01927## 1508 9.35 10 ##STR01928## 1509 8.61
10
##STR01929## 1510 9.06 10 ##STR01930## 1511 7.94 10 ##STR01931##
1512 8.45 10 ##STR01932## 1513 10.16 10 ##STR01933## 1514 10.56 10
##STR01934## 1515 10.50 10 ##STR01935## 1516 9.70 10 ##STR01936##
1517 11.38 10 ##STR01937## 1518 11.54 10 ##STR01938## 1519 10.97 10
##STR01939## 1520 10.52 10 ##STR01940## 1521 11.01 10 ##STR01941##
1522 11.24 10 ##STR01942## 1523 9.21 10 ##STR01943## 1524 10.76 10
##STR01944## 1525 10.04 10 ##STR01945## 1526 10.08 10 ##STR01946##
1527 11.68 10 ##STR01947## 1528 10.18 10 ##STR01948## 1529 10.60 10
##STR01949## 1530 10.08 10 ##STR01950## 1531 10.25 10 ##STR01951##
1532 10.06 10 ##STR01952## 1533 10.51 10 ##STR01953## 1534 10.84 10
##STR01954## 1535 10.52 10 ##STR01955## 1536 10.96 10 ##STR01956##
1537 10.48 10 ##STR01957## 1538 10.61 10 ##STR01958## 1539 8.19 28
##STR01959## 1540 8.59 28 ##STR01960## 1541 9.61 28 ##STR01961##
1542 8.99 28 ##STR01962## 1543 5.99 28 ##STR01963## 1544 9.60 28
##STR01964## 1545 8.89 28 ##STR01965## 1546 9.44 28 ##STR01966##
1547 9.55 28 ##STR01967## 1548 9.04 28 ##STR01968## 1549 9.48 28
##STR01969## 1550 9.03 28 ##STR01970## 1551 8.48 28 ##STR01971##
1552 10.98 10 ##STR01972## 1553 7.81 28
Biological Assays
Assay Procedures
GLP-1 PAM Shift cAMP Assay: Dose Response of Peptide Ligand in
Presence of Fixed Concentration of Compound.
A GLP-1R expressing CRB-bla CHO-K1 cell line was purchased from
Invitrogen. Cells were seeded into 384-well white flat bottom
plates at 5000 cells/well/20 .mu.L growth media (DMEM-High glucose,
10% dialyzed FBS, 0.1 mM NEAA, 25 mM Hepes, 100 U/mL penicillin/100
.mu.g/mL streptomycin, 5 .mu.g/mL Blasticidin, 600 .mu.g/mL
Hygromycin) and incubated for 18 h at 37.degree. C. in 5% CO.sub.2.
Growth medium was replaced with 12 .mu.L assay buffer (Hanks
Balanced Salt solution, 10 mM Hepes, 0.1% BSA, pH 7.4). A 5.times.
peptide dose response curve (12-point) was generated in assay
buffer containing 1.5 mM IBMX, 12.5% DMSO, and 50 .mu.M compound.
Peptide ligand was GLP-1(9-36). The 5.times. peptide dose response
plus compound mix was added (3 .mu.L) and cells were incubated for
30 min at 37.degree. C. Direct detection of cAMP was carried out
using DiscoveRx HitHunter cAMP kit according to manufacturer's
instructions and luminescence was read using a SpectraMax M5 plate
reader. Luminescence was analyzed by non-linear regression to
determine the EC.sub.50 and Emax. A GLP-1(7-36) dose response was
included to determine maximum efficacy.
EC.sub.20 GLP-1(9-36) PAM cAMP Assay: Dose Response of Compound in
the Presence of Fixed Concentration of GLP-1 (9-36).
GLP-1R CRE-bla CHO-K1 cells cultured in growth medium (DMEM-High
glucose, 10% dialyzed FBS, 0.1 mM NEAA, 25 mM Hepes, 100 U/mL
penicillin/100 .mu.g/mL streptomycin, 5 .mu.g/mL Blasticidin, 600
.mu.g/mL Hygromycin) were trypsinized and plated in suspension into
384 well white flat bottom plates at 5000 cells/well in 12 .mu.L
assay buffer (Hanks Balanced Salt solution, 10 mM hepes, 0.1% BSA,
pH 7.4). A 5.times. compound dose response curve (12-point) was
generated in assay buffer containing 1.5 mM IBMX, 4% DMSO.
GLP-1(9-36) was diluted to 4.2 .mu.M in assay buffer containing 1.5
mM IMBX and 4% DMSO. The 5.times. compound dose response was added
(3 .mu.L), followed by 0.5 .mu.L of GLP-1(9-36) and cells were
incubated for 30 min at 37.degree. C. Direct detection of cAMP was
carried out using DiscoveRx HitHunter cAMP kit according to
manufacturer's instructions and luminescence was read using a
SpectraMax M5 plate reader. Luminescence was converted to total
cAMP using a cAMP standard curve and data was analyzed by
non-linear regression to determine the EC.sub.50 and Emax.
Peptide Sequences
GLP-1(7-36): HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH.sub.2 (SEQ ID NO:
2). GLP-1(9-36): EGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH.sub.2 (SEQ ID NO:
3). GLP-1(7-36) was purchased from GenScript. GLP-1(9-36) was
purchased from Biopeptide Co., Inc.
Reported GLP-1 Activity
Activity data for selected GLP-1 modulators are displayed in Table
2. The EC.sub.20GLP-1(9-36) PAM Activity range is denoted as
follows: + denotes activity <0.8 .mu.M, ++ denotes activity
between 0.8 and 2.5 .mu.M, +++ denotes activity between 2.5 and 5
.mu.M, and ++++ denotes activity 5 to 10 .mu.M.
TABLE-US-00002 TABLE 2 Activity Data COMPOUND EC.sub.20 GLP-1(9-36)
NUMBER PAM EC.sub.50 1 ++ 2 +++ 3 ++++ 4 ++++ 5 +++ 6 ++++ 7 ++++ 8
++ 9 ++++ 10 +++ 11 ++ 13 ++ 14 +++ 15 +++ 16 ++++ 17 +++ 18 ++ 19
++ 20 ++ 21 +++ 22 +++ 23 +++ 24 ++ 25 ++ 26 +++ 27 ++ 28 +++ 29 ++
30 ++ 31 ++ 32 ++++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++ 38 ++ 39 ++
40 +++ 41 +++ 42 +++ 43 +++ 44 +++ 45 ++ 46 ++ 47 +++ 48 ++++ 49
++++ 50 +++ 51 +++ 52 ++ 53 +++ 54 +++ 55 +++ 56 +++ 57 +++ 58 +++
59 +++ 60 +++ 61 +++ 62 +++ 63 ++ 64 ++ 65 +++ 66 +++ 67 ++ 68 +++
69 ++++ 70 ++++ 71 +++ 72 ++++ 73 ++ 74 +++ 75 +++ 76 ++ 77 ++ 78
++ 79 ++ 80 ++ 81 ++++ 82 ++ 83 ++ 84 ++ 85 ++ 86 ++ 87 ++ 88 ++++
89 ++ 90 +++ 91 ++ 92 ++ 93 ++++ 94 ++ 95 ++ 96 +++ 97 ++ 98 ++ 99
++ 100 ++ 101 ++ 102 ++ 104 ++ 105 ++++ 106 ++ 107 ++ 108 ++ 109 ++
110 ++ 111 ++ 112 ++ 113 ++ 114 ++ 115 ++ 116 ++ 117 + 118 + 119 +
120 ++ 121 ++ 122 ++ 123 ++ 124 ++ 125 ++ 126 ++ 127 ++ 128 ++ 129
++ 130 + 131 ++ 132 ++ 133 ++ 134 ++ 135 ++ 136 ++++ 137 ++ 138 ++
139 ++ 140 +++ 141 ++ 142 + 143 + 144 ++ 145 ++ 146 +++ 147 +++ 148
++ 149 ++ 150 ++ 151 ++ 152 ++ 153 ++ 154 + 155 ++ 156 ++ 157 ++
158 + 159 ++ 160 ++ 161 ++ 162 ++ 163 ++ 164 ++ 165 ++ 166 ++ 167
++ 168 ++ 169 ++++ 170 ++ 171 ++ 172 ++ 173 ++ 174 + 175 + 176 ++++
177 ++ 178 ++ 179 ++++ 180 + 181 ++ 182 ++ 183 ++ 184 ++ 185 ++ 186
++ 187 +++ 188 +++ 189 ++ 190 +++ 191 ++ 192 + 193 ++ 194 ++ 195 ++
196 +++ 197 +++ 198 ++++ 199 ++ 200 +++ 201 +++ 202 ++++ 203 ++++
204 +++ 205 ++ 206 +++ 207 +++ 208 +++ 209 ++ 210 +++ 211 ++++ 212
++++ 213 +++ 214 +++ 215 +++ 216 +++ 217 ++++ 218 +++ 219 ++ 220
+++ 221 +++ 222 ++ 223 ++ 224 ++ 225 + 226 ++ 227 +++ 228 ++ 229 ++
230 ++ 231 ++++ 232 ++ 233 +++ 234 ++++ 235 +++ 236 ++++ 237 ++ 238
++ 239 ++ 240 +++ 241 ++ 242 ++ 243 ++ 244 +++ 245 ++ 246 ++
247 ++ 248 +++ 249 ++++ 250 ++ 251 ++++ 252 ++++ 253 +++ 254 ++ 255
++++ 256 ++++ 257 ++ 258 ++++ 259 ++ 260 + 261 +++ 262 +++ 263 ++
264 ++ 265 ++++ 266 ++++ 267 ++ 268 ++ 269 ++ 270 +++ 271 ++ 272 ++
273 ++ 274 ++ 275 ++ 276 ++ 277 + 278 +++ 279 ++++ 280 +++ 281 +
282 ++ 283 ++++ 284 ++ 285 ++ 286 +++ 287 ++++ 288 +++ 289 +++ 291
++ 292 ++ 293 +++ 294 ++ 295 ++ 296 ++ 297 + 298 + 299 + 300 + 301
++ 302 +++ 303 ++ 304 ++ 305 ++ 306 + 307 ++ 308 ++ 309 + 310 + 311
++ 312 ++ 313 ++ 314 ++ 315 ++ 316 + 317 + 318 + 319 + 320 + 321 +
322 ++ 323 + 324 ++ 325 ++++ 326 + 327 + 328 + 329 ++ 330 ++ 331 ++
332 ++ 333 + 334 ++ 335 ++ 336 + 337 ++ 338 ++ 339 ++ 340 ++ 341 +
342 ++ 343 ++ 344 + 345 + 346 ++ 347 + 348 ++ 349 + 350 + 351 + 352
+ 353 ++ 354 + 355 ++ 356 ++ 357 ++ 358 ++ 359 ++ 360 ++ 361 ++ 362
+++ 363 ++ 364 ++ 365 +++ 366 +++ 367 ++ 368 + 369 ++ 370 ++ 371 +
372 + 373 ++ 374 ++ 375 + 376 ++ 377 + 378 + 379 + 380 ++ 381 ++
382 ++ 383 +++ 384 ++++ 385 ++++ 386 ++ 387 ++++ 388 +++ 389 ++ 390
++ 391 +++ 392 +++ 393 ++ 394 +++ 395 ++ 396 + 397 +++ 398 + 399 +
400 + 401 + 402 + 403 ++ 404 + 405 + 406 ++ 407 + 408 ++ 409 ++ 410
++ 411 ++ 412 + 413 ++++ 414 + 415 + 416 + 417 + 418 + 419 + 420 +
421 ++ 422 + 423 ++ 424 + 425 +++ 426 ++ 427 ++ 428 ++ 429 +++ 430
++++ 431 + 432 + 433 +++ 434 ++ 435 ++ 436 + 437 + 438 ++++ 439 +++
440 + 441 ++ 442 ++ 443 ++ 444 + 445 + 446 ++ 447 ++ 448 + 449 ++
450 + 451 + 452 +++ 453 ++ 454 ++ 455 + 456 ++ 457 +++ 458 ++ 459
++ 460 ++++ 461 ++ 462 ++++ 463 ++++ 464 ++++ 465 ++ 466 ++ 467 +
468 + 469 ++ 470 + 471 ++++ 472 ++ 473 ++++ 474 ++ 475 ++ 476 +++
477 + 478 + 479 + 480 ++ 481 ++ 482 + 483 ++ 484 ++ 485 ++++ 486 +
487 + 488 ++ 489 ++ 490 ++ 491 + 492 ++++ 493 + 494 + 495 + 496 +
497 + 498 ++
499 + 500 ++ 501 + 502 + 503 ++ 504 +++ 505 ++ 506 ++ 507 ++ 508 +
509 ++ 510 +++ 511 ++ 512 + 513 + 514 + 515 + 516 + 517 + 518 ++
519 ++ 520 ++ 521 + 522 ++ 523 + 524 + 525 + 526 + 527 + 528 + 529
+ 530 + 531 ++ 532 + 533 + 534 ++ 535 ++++ 536 ++ 537 ++++ 538 ++++
539 ++++ 540 + 541 ++ 542 + 543 + 544 + 545 + 546 ++ 547 ++ 548 +
549 + 550 ++ 551 + 552 ++ 553 ++ 554 + 555 +++ 556 + 557 + 558 +
559 ++++ 560 ++ 561 + 562 + 563 + 564 ++ 565 ++ 566 + 567 + 568 +
569 + 570 + 571 ++ 572 ++ 573 ++ 574 ++ 575 +++ 576 ++ 577 +++ 578
+++ 579 + 580 + 581 ++ 582 ++ 583 ++++ 584 ++ 585 ++ 586 + 587 +
588 ++ 589 ++ 590 + 591 + 592 ++ 593 + 594 + 595 + 596 ++ 597 + 598
+ 599 + 600 + 601 ++ 602 + 603 ++ 604 ++ 605 + 606 ++ 607 ++ 608 ++
609 + 610 + 611 + 612 + 613 ++ 614 ++ 615 ++++ 616 ++ 617 + 618
++++ 619 ++ 620 ++++ 621 +++ 622 ++ 623 ++ 624 + 625 + 626 + 627 +
628 ++ 629 ++ 630 + 631 ++ 632 ++ 633 ++ 634 + 635 + 636 + 637 ++
638 +++ 639 + 640 + 641 + 642 + 644 + 645 + 646 + 647 + 648 ++ 649
++ 650 + 651 + 652 + 653 + 654 + 655 ++ 656 ++ 657 ++ 658 + 659 +
660 ++ 661 + 662 + 663 ++ 664 +++ 665 ++ 666 ++ 667 ++ 668 ++ 669
++ 670 +++ 671 +++ 672 +++ 673 ++++ 674 ++++ 675 ++++ 676 +++ 677
+++ 678 ++ 679 ++ 680 ++++ 681 ++++ 682 +++ 683 ++ 684 ++++ 685 +++
686 +++ 687 +++ 688 +++ 689 +++ 690 +++ 691 +++ 692 ++++ 693 ++++
694 +++ 695 +++ 696 +++ 697 +++ 698 + 699 ++++ 700 ++++ 701 +++ 702
++ 703 + 704 ++ 705 ++ 706 ++ 707 ++++ 708 ++ 709 ++ 710 ++++ 711
+++ 712 ++ 713 ++ 714 +++ 715 +++ 716 ++ 717 ++ 718 +++ 719 ++ 720
+++ 721 ++ 722 ++ 723 ++ 724 ++ 725 ++ 726 ++ 727 +++ 728 ++ 729 ++
730 +++ 731 +++ 732 ++ 733 ++ 734 ++ 735 ++ 736 + 737 + 738 + 739 +
740 +++ 741 +++ 742 +++ 743 ++++ 744 ++++ 745 ++ 746 +++ 747 +++
748 +++ 749 ++ 750 +++
751 +++ 752 ++++ 753 +++ 754 ++++ 755 +++ 756 ++++ 757 ++ 758 +++
759 ++ 760 ++ 761 +++ 762 ++++ 763 ++ 764 + 765 ++ 766 +++ 767 +++
768 ++ 769 ++++ 770 + 771 ++ 772 + 773 ++ 774 ++ 775 + 776 + 777 ++
778 + 779 ++ 780 +++ 781 +++ 782 ++ 783 ++ 784 ++++ 785 +++ 786 ++
787 ++ 788 ++++ 789 +++ 790 ++ 791 ++ 792 ++ 793 ++ 794 ++ 795 +
796 + 797 ++ 798 ++ 799 ++ 800 ++++ 801 ++++ 802 +++ 803 ++ 804 ++
806 ++ 807 ++++ 808 +++ 809 ++ 810 ++++ 811 ++ 812 ++ 813 ++ 814 ++
815 + 816 ++ 817 ++ 818 ++ 819 +++ 820 +++ 821 ++ 822 +++ 823 ++
824 + 825 + 826 +++ 827 ++ 828 + 829 ++++ 830 ++++ 832 +++ 833 ++++
834 ++ 835 +++ 836 +++ 837 + 838 ++ 839 ++ 840 ++ 841 ++ 842 ++ 843
++ 844 ++ 845 +++ 846 +++ 847 +++ 848 +++ 849 +++ 850 +++ 851 +++
852 +++ 853 ++ 855 ++ 856 ++ 857 ++++ 858 ++ 859 +++ 860 ++ 861 +++
862 ++ 863 ++ 864 ++ 865 ++ 866 +++ 867 ++ 868 ++ 869 +++ 870 ++
871 +++ 872 ++ 873 + 874 ++ 875 ++ 876 ++ 877 ++ 878 + 879 +++ 880
+ 881 ++ 882 ++ 883 ++++ 884 ++ 885 ++++ 886 ++ 887 + 888 ++ 889 ++
890 ++ 891 ++ 892 + 893 +++ 894 ++++ 895 + 896 ++++ 897 ++++ 898
+++ 899 +++ 900 ++ 901 ++ 902 +++ 903 ++++ 904 +++ 905 ++++ 906 +++
907 ++ 908 ++ 909 +++ 910 ++ 911 ++ 912 + 913 + 914 +++ 915 ++ 916
++ 917 ++ 918 ++++ 919 ++++ 920 ++ 921 ++++ 922 ++++ 923 ++ 924 +++
925 +++ 926 ++ 927 +++ 928 +++ 929 ++++ 930 ++++ 931 +++ 932 +++
933 ++++ 934 ++++ 935 +++ 936 ++ 937 ++ 938 ++++ 939 +++ 940 ++ 941
+++ 942 +++ 943 ++ 944 + 945 + 946 +++ 947 ++ 948 +++ 949 ++ 950 ++
951 ++ 952 +++ 953 ++ 954 ++ 955 ++++ 956 +++ 957 ++ 958 ++ 959 ++
960 ++ 961 +++ 962 ++ 963 ++++ 964 +++ 965 ++++ 966 ++++ 967 +++
968 ++++ 969 +++ 970 +++ 971 +++ 972 ++++ 973 ++++ 974 +++ 975 ++++
976 +++ 977 ++++ 978 ++ 979 +++ 980 ++ 981 +++ 982 ++++ 983 ++++
984 +++ 985 +++ 986 ++ 987 ++++ 988 ++++ 989 ++ 990 +++ 991 ++ 992
+++ 993 +++ 994 ++ 995 ++++ 996 ++ 997 ++++ 998 +++ 999 +++ 1000
++++ 1001 +++ 1002 ++ 1003 ++++ 1004 ++
1005 ++ 1006 ++ 1007 ++ 1008 ++++ 1009 +++ 1010 +++ 1011 +++ 1012
+++ 1013 ++++ 1014 ++++ 1015 ++ 1016 ++++ 1017 +++ 1018 ++++ 1019
+++ 1020 ++++ 1021 +++ 1022 +++ 1023 +++ 1024 ++ 1025 ++ 1026 +++
1027 ++++ 1028 +++ 1029 +++ 1030 ++++ 1031 +++ 1032 ++ 1033 ++++
1034 +++ 1035 ++ 1036 +++ 1037 ++ 1038 +++ 1039 ++ 1040 ++++ 1041
++ 1042 ++++ 1043 +++ 1044 +++ 1045 +++ 1046 ++ 1047 +++ 1048 +++
1049 ++ 1050 ++ 1051 ++++ 1052 +++ 1053 +++ 1054 +++ 1055 +++ 1056
+ 1057 + 1058 + 1059 ++++ 1060 +++ 1061 +++ 1062 ++ 1063 + 1064 ++
1065 + 1066 ++ 1067 ++ 1068 ++ 1069 ++ 1070 ++ 1071 +++ 1072 ++
1073 ++ 1074 ++ 1075 ++ 1076 +++ 1077 ++ 1078 +++ 1079 +++ 1080 ++
1081 ++ 1082 ++ 1083 ++ 1084 + 1085 ++ 1086 ++ 1087 + 1088 + 1089
++ 1090 + 1091 ++ 1092 ++ 1093 + 1094 + 1095 +++ 1096 ++ 1097 ++
1098 +++ 1099 ++ 1100 +++ 1101 ++ 1102 ++ 1103 ++ 1104 ++ 1105 +++
1106 +++ 1107 ++ 1108 + 1109 ++ 1110 ++ 1111 ++ 1112 ++ 1113 ++
1114 ++ 1115 ++ 1116 ++ 1117 ++ 1118 ++ 1119 ++ 1120 +++ 1121 ++
1122 ++++ 1123 ++ 1124 + 1125 ++ 1126 ++ 1127 ++ 1128 + 1129 ++
1130 ++ 1131 ++ 1132 ++ 1133 + 1134 ++ 1135 ++ 1136 ++ 1137 + 1138
+ 1139 + 1140 + 1141 + 1142 + 1143 + 1144 ++ 1145 + 1146 + 1147 +
1148 + 1149 ++++ 1150 + 1151 + 1152 + 1153 + 1154 + 1155 + 1156 +
1157 + 1158 + 1159 + 1160 + 1161 ++ 1162 +++ 1163 + 1164 + 1165 +
1166 + 1167 + 1168 + 1169 + 1170 + 1171 + 1172 ++ 1173 + 1174 +
1175 + 1176 + 1177 + 1178 + 1179 + 1180 +++ 1181 ++ 1182 + 1183 +
1184 + 1185 + 1186 + 1187 + 1188 + 1189 + 1190 + 1191 + 1192 + 1193
+ 1194 + 1195 + 1196 + 1197 ++ 1198 + 1199 + 1200 + 1201 + 1202
++++ 1203 + 1204 + 1205 + 1206 ++ 1207 + 1208 + 1209 + 1210 + 1211
+ 1212 + 1213 + 1214 +++ 1215 + 1216 + 1217 + 1218 + 1219 + 1220 +
1221 + 1222 + 1223 + 1224 + 1225 + 1226 + 1227 ++ 1228 ++ 1229 +++
1230 ++ 1231 ++ 1232 ++ 1233 ++ 1234 +++ 1235 +++ 1236 ++ 1237 +++
1238 ++ 1239 ++ 1240 ++ 1241 ++ 1242 ++ 1243 ++ 1244 +++ 1245 +++
1246 + 1247 ++ 1248 ++++ 1249 +++ 1250 ++ 1251 ++++ 1252 ++ 1253 +
1254 ++ 1255 +++
1256 ++++ 1257 +++ 1258 ++ 1259 ++++ 1260 ++ 1261 ++ 1262 ++ 1263
+++ 1264 ++ 1265 + 1266 +++ 1267 ++++ 1268 + 1269 ++++ 1270 ++ 1271
++ 1272 ++++ 1273 ++++ 1274 +++ 1275 ++ 1276 ++ 1277 ++ 1278 + 1279
+++ 1280 + 1281 +++ 1282 + 1283 + 1284 ++ 1285 + 1286 + 1287 ++
1288 ++ 1289 + 1290 +++ 1291 ++ 1292 + 1293 + 1294 ++ 1295 ++ 1296
+++ 1297 +++ 1298 + 1299 ++ 1300 ++ 1301 ++++ 1302 ++++ 1303 ++++
1304 ++ 1305 + 1306 ++ 1307 ++ 1308 ++ 1309 ++ 1310 +++ 1311 +++
1312 ++ 1313 + 1314 + 1315 + 1316 + 1317 + 1318 + 1319 ++++ 1320 +
1321 ++ 1322 + 1323 + 1324 + 1325 + 1326 + 1327 + 1328 ++ 1329 +
1330 + 1331 + 1332 + 1333 +++ 1334 + 1335 +++ 1336 +++ 1337 + 1338
+++ 1339 + 1340 + 1341 + 1342 ++ 1343 + 1344 ++ 1345 ++ 1346 + 1347
+ 1348 +++ 1349 ++++ 1350 +++ 1351 +++ 1352 ++ 1353 ++++ 1354 +++
1355 + 1356 + 1357 +++ 1358 +++ 1359 ++ 1360 +++ 1361 ++ 1362 +
1363 + 1364 + 1365 + 1366 + 1367 + 1368 + 1369 ++ 1370 ++ 1371 ++
1372 ++ 1373 + 1374 ++ 1375 ++ 1376 ++ 1377 ++ 1378 + 1379 + 1380
++ 1381 ++++ 1382 ++ 1383 ++ 1384 ++ 1385 ++++ 1386 ++ 1387 + 1388
++ 1389 + 1390 ++++ 1391 + 1392 ++ 1393 ++ 1394 + 1395 + 1396 +
1397 + 1398 + 1399 + 1400 + 1401 + 1402 + 1403 + 1404 + 1405 + 1406
+ 1407 + 1408 + 1409 + 1410 + 1411 ++ 1412 + 1413 + 1414 + 1415
++++ 1416 + 1417 ++ 1418 ++++ 1419 + 1420 +++ 1421 + 1422 ++ 1423
++ 1424 + 1425 ++ 1426 ++ 1427 + 1428 + 1429 + 1430 + 1431 + 1432 +
1433 + 1434 ++++ 1435 ++ 1436 ++ 1437 + 1438 + 1439 + 1440 ++++
1441 ++ 1442 + 1443 + 1444 + 1445 + 1446 + 1447 + 1448 ++++ 1449 +
1450 + 1451 ++ 1452 + 1453 + 1454 + 1455 + 1456 + 1457 + 1458 +
1459 + 1460 + 1461 + 1462 ++ 1463 + 1464 + 1465 + 1466 + 1467 +
1468 + 1469 + 1470 + 1471 + 1472 + 1473 + 1474 + 1475 + 1476 + 1477
+ 1478 ++ 1479 ++ 1480 ++ 1481 + 1482 ++ 1483 ++ 1484 ++ 1485 +
1486 ++ 1487 ++ 1488 ++ 1489 + 1490 ++ 1491 ++ 1492 ++ 1493 + 1494
++ 1495 ++ 1496 ++ 1497 +++ 1498 ++ 1499 +++ 1500 ++++ 1501 ++++
1502 +++ 1503 ++ 1504 ++ 1505 ++ 1506 ++++
1507 ++ 1508 + 1509 ++++ 1510 +++ 1511 + 1512 + 1513 + 1514 + 1515
+ 1516 + 1517 + 1518 + 1519 + 1520 + 1521 + 1522 + 1523 ++ 1524 +
1525 + 1526 + 1527 ++ 1528 ++ 1529 + 1530 ++ 1531 + 1532 + 1533 +
1534 + 1535 ++ 1536 + 1537 + 1538 ++ 1539 +++ 1540 + 1541 ++ 1542 +
1543 + 1544 + 1545 + 1546 + 1547 + 1548 + 1549 + 1550 + 1551 +++
1552 ++ 1553 ++
In Vivo Assays
In Vivo Procedures
The Oral Glucose Tolerance Test in C57Bl/6 Mice.
Fasted C57BL/6 female mice are 8-10 weeks of age. Sitagliptin,
compound, or vehicle is dosed at least 1 hr prior to the oGTT. Mice
receive a bolus of glucose (3 g/kg) by oral gavage (time 0). Blood
samples are collected at frequent time intervals from the tail tip
for glucose measurement (BD glucometer; Becton-Dickinson, Lincoln
Park, N.J.).
The Oral Glucose Tolerance Test in Ob/Ob Mice
Fasted ob/ob female mice are 7-10 weeks of age. Sitagliptin,
compound, or vehicle is dosed at least 1 hr prior to the oGTT. Mice
receive a bolus of glucose (0.2 g/kg) by oral gavage (time 0).
Blood samples are collected at frequent time intervals from the
tail tip for glucose measurement (BD glucometer; Becton-Dickinson,
Lincoln Park, N.J.).
The Oral Glucose Tolerance Test in Fa/Fa Rats.
The use of the compounds of this invention to lower glucose can be
evaluated in rats using the protocol described by Pederson et. al.
(Diabetes, Vol. 47, August 1998, 1253-1258). After an overnight
fast, lean or obese animals are administered oral glucose by
syringe and feeding tube (1 g/kg) as a 40% solution (wt/vol).
Compound is dissolved and administered along with the glucose. In
control experiments, vehicle is administered along with oral
glucose. Blood samples are collected from the tail veins of
conscious unrestrained rats into heparinized capillary tubes at 0
and 5, 10, 20, 30, and 60 min after glucose administration. Blood
samples are centrifuged at 4.degree. C., and plasma is stored at
-20.degree. C. until analysis for glucose and insulin measurement.
Glucose levels are measured using the glucose oxidase procedure
(Beckman glucose analyzer; Fullerton, Calif.).
The various embodiments described above can be combined to provide
further embodiments. All of the U.S. patents, U.S. patent
application publications, U.S. patent applications, foreign
patents, foreign patent applications and non-patent publications
referred to in this specification and/or listed in the Application
Data Sheet, are incorporated herein by reference, in their
entirety. Aspects of the embodiments can be modified, if necessary
to employ concepts of the various patents, applications and
publications to provide yet further embodiments. These and other
changes can be made to the embodiments in light of the
above-detailed description. In general, in the following claims,
the terms used should not be construed to limit the claims to the
specific embodiments disclosed in the specification and the claims,
but should be construed to include all possible embodiments along
with the full scope of equivalents to which such claims are
entitled. Accordingly, the claims are not limited by the
disclosure.
SEQUENCE LISTINGS
1
3131PRTArtificial SequenceSequence included in GLP-1agonist is
liraglutide 1His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr
Leu Glu Gly 1 5 10 15Gln Ala Ala Lys Glu Phe Ile Ala Trp Lys Val
Arg Gly Arg Gly 20 25 30230PRTArtificial SequenceGLP-1(7-36)
sequence 2His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu
Glu Gly 1 5 10 15Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys
Gly Arg 20 25 30328PRTArtificial SequenceGLP-1(9-36) sequence 3Glu
Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala 1 5 10
15Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg 20 25
* * * * *